Proteopedia - User contributions [en]

Sean Swale/Human Thrombin Inhibitor

2012-11-16T20:18:43Z

Sean Swale:

<StructureSection load='3utu' size='500' frame='false' align='right' |caption='Human Thrombin' scene=''>

===Reasons to develop another <scene name='Sean_Swale/Human_Thrombin_Inhibitor/Active_site/3'>Thrombin</scene> Inhibitor===
Thrombin is a serine protease that cleaves fibrinogen to allow fibrin to form stringy networks that trap red blood cells to form clots. Thrombin is a serine protease because it cleaves fibrinogen with its serine residue. Thrombin when made by the body is tethered to blood vessels so that it cannot cause clots throughout the body causing strokes and heart attacks. Additionally, thrombin is only activated for a few seconds to limit the clotted area to the injured area<ref>January 2002 Molecule of the Month by David Goodsell http://www.rcsb.org/pdb/101/motm.do?momID=25 </ref>. However, when fibrin has accumulated at an injury site, sometimes it will break away and occlude a blood vessel which can cause stroke or heart attack. In order to prevent venous thrombosis, blood clots, after surgery or during dialysis when blood is in contact with artificial devices, Heparin is normally administered. Unfortunately Heparin is neutralized by plasma proteins in the blood, is less efficient for the inhibition of clot bound thrombin, and can trigger an enormous immune response. Antithrombotic drugs like Hirudin will be given if Heparin is not able to be tolerated or if the person receives regular dialysis. Hirudin administration require large doses to maintain proper inhibition of Thrombin which heavily taxes the body. Chemists have been working on designer drugs to increase selectivity and potency. One compound which has shown great selectivity and potency in vitro is <scene name='Sean_Swale/Human_Thrombin_Inhibitor/Inhibitor_65/1'>inhibitor 65</scene>.<ref> DOI: 10.1002/cmdc.201200292</ref>

----

===Phe-Pro-p-amidinobenzylamine===
An early experiment to find a better thrombin inhibitor yielded a structure that was able to bond to the P1 and P2 sites of Thrombin effectively. In 1996 Lilly research laboratories created D-Phe-Pro-p-amidinobenzylamine by making improvements on the previous structure D-Phe-Pro-Agmatine. The new compound they created bonded to thrombin 130x more than it did to trypsin (also a serine protease), and it was highly selective of thrombin over fibrinolytic enzymes which break down fibrin clots. The inhibitor bound with Thrombin at rates 26,000x greater than with plasmin,<ref> http://voices.yahoo.com/what-fibrinolytic-enzymes-6186058.html?cat=68</ref>, 170,000x greater than with t-Pa, and 400,000x greater than with urokinase.
[[Image:1996 inhibitor rates.png|left|frame|100|Inhibitor 12 is the identical P1 and P2 sites of Inhibitor 65.(1996)<ref> M. R. Wiley, N. Y. Chirgadze, D. K. Clawson, T. J. Craft, D. S. GiffordMoore, N. D. Jones, J. L. Olkowski, L. C. Weir, G. F. Smith, Bioorg. Med. Chem. Lett. 1996, 6, 2387. http://www.sciencedirect.com/science/article/pii/0960894X96004428 </ref>]]
Its selectivity was gained by binding its nitrogens on the benzamidine <scene name='Sean_Swale/Human_Thrombin_Inhibitor/P1_residue/1'>group</scene> by hydrogen bonding to Asp 189, and by fitting its benzamidine benzene into a hydrophobic pocket with Ser 214-Glu 217 and Asp 189-Glu 192 on the other side. The <scene name='Sean_Swale/Human_Thrombin_Inhibitor/P2_proline/1'>proline</scene> residue is in another hydrophobic pocket made up of His 57, Tyr 60A, Leu 99, and Trp 60D. The rest of this structure is unimportant on review of inhibitor 65 because only the amidinobenzylamine which occupies R1 and the proline which occupies the R2 sit are the same residues on inhibitor 65.<ref> M. R. Wiley, N. Y. Chirgadze, D. K. Clawson, T. J. Craft, D. S. GiffordMoore, N. D. Jones, J. L. Olkowski, L. C. Weir, G. F. Smith, Bioorg. Med. Chem. Lett. 1996, 6, 2387. http://www.sciencedirect.com/science/article/pii/0960894X96004428 </ref>

----

===P3 and P4 of Inhibitor 65===
[[Image:Inhibitor 65.png|center|200px|frame|<ref> DOI: 10.1002/cmdc.201200292</ref> ]]
Inhibitor 65 additionally has a <scene name='Sean_Swale/Human_Thrombin_Inhibitor/P4/1'>P4</scene> sulfonyl group with a methoxy group at the end of the residue. The residue sits in a hydrophobic <scene name='Sean_Swale/Human_Thrombin_Inhibitor/P4_binding_pocket/1'>pocket</scene>. It sits in tight VanderWaals structure with the surrounding residues Leu 99, Tyr 60A, Arg 97, Glu 97, and Asn 98.The <scene name='Sean_Swale/Human_Thrombin_Inhibitor/P4_sulfonyl/1'>sulfonyl</scene> group holds its own VanderWaal forces. Additionally, the <scene name='Sean_Swale/Human_Thrombin_Inhibitor/P4_chlorine/1'>chlorine</scene> points to the carbonyl oxygen of Asn 98 and there is a weak Cl-π bond with Trp 215. For the P3 <scene name='Sean_Swale/Human_Thrombin_Inhibitor/P3_binding_site/6'>residue</scene>, there the backbone of asparagine forms and anti parallel beta sheet with Gly 216. The alkylated asparagine’s NH binds to a water molecule which then connects to Glu 192, and the hydrogens of Gly 219 and Gly 216.
[[Image:Thrombin1.gif|left|frame|200px|a) Stereo view of the complete inhibitor structure provided with its electron density in the active site of thrombin. Thrombin is shown with its solvent- accessible surface. b) The P4 sulfonyl residue is located in the aryl binding pocket. The chlorine atom points to the carbonyl oxygen of Asn 98 and accommodates a position above the indole moiety of Trp 215. The methoxy group perfectly fills the upper niche of the S3/4 pocket. c) The P3 side chain is directed into the solvent, where its amide NH binds via a bridging water molecule to Glu 192, Gly 216 and Gly 219.<ref> DOI: 10.1002/cmdc.201200292</ref> ]]

</StructureSection>
This is the <scene name='Sean_Swale/Human_Thrombin_Inhibitor/Thrombin_active_site/2'>active site</scene> of thrombin

[[Image:1ppb-transparent.gif|right|500px|frame|Thrombin with serine residue visible.<ref>January 2002 Molecule of the Month by David Goodsell http://www.rcsb.org/pdb/101/motm.do?momID=25 </ref>]]

==References==
{{reflist}}

Sean Swale/Human Thrombin Inhibitor

2012-11-16T20:17:59Z

Sean Swale:

<StructureSection load='3utu' size='500' frame='false' align='right' |caption='Human Thrombin' scene=''>

===Reasons to develop another <scene name='Sean_Swale/Human_Thrombin_Inhibitor/Active_site/3'>Thrombin</scene> Inhibitor===
Thrombin is a serine protease that cleaves fibrinogen to allow fibrin to form stringy networks that trap red blood cells to form clots. Thrombin is a serine protease because it cleaves fibrinogen with its serine residue. Thrombin when made by the body is tethered to blood vessels so that it cannot cause clots throughout the body causing strokes and heart attacks. Additionally, thrombin is only activated for a few seconds to limit the clotted area to the injured area<ref>January 2002 Molecule of the Month by David Goodsell http://www.rcsb.org/pdb/101/motm.do?momID=25 </ref>. However, when fibrin has accumulated at an injury site, sometimes it will break away and occlude a blood vessel which can cause stroke or heart attack. In order to prevent venous thrombosis, blood clots, after surgery or during dialysis when blood is in contact with artificial devices, Heparin is normally administered. Unfortunately Heparin is neutralized by plasma proteins in the blood, is less efficient for the inhibition of clot bound thrombin, and can trigger an enormous immune response. Antithrombotic drugs like Hirudin will be given if Heparin is not able to be tolerated or if the person receives regular dialysis. Hirudin administration require large doses to maintain proper inhibition of Thrombin which heavily taxes the body. Chemists have been working on designer drugs to increase selectivity and potency. One compound which has shown great selectivity and potency in vitro is <scene name='Sean_Swale/Human_Thrombin_Inhibitor/Inhibitor_65/1'>inhibitor 65</scene>.<ref> DOI: 10.1002/cmdc.201200292</ref>

----

===Phe-Pro-p-amidinobenzylamine===
An early experiment to find a better thrombin inhibitor yielded a structure that was able to bond to the P1 and P2 sites of Thrombin effectively. In 1996 Lilly research laboratories created D-Phe-Pro-p-amidinobenzylamine by making improvements on the previous structure D-Phe-Pro-Agmatine. The new compound they created bonded to thrombin 130x more than it did to trypsin (also a serine protease), and it was highly selective of thrombin over fibrinolytic enzymes which break down fibrin clots. The inhibitor bound with Thrombin at rates 26,000x greater than with plasmin,<ref> http://voices.yahoo.com/what-fibrinolytic-enzymes-6186058.html?cat=68</ref>, 170,000x greater than with t-Pa, and 400,000x greater than with urokinase.
[[Image:1996 inhibitor rates.png|left|100|Inhibitor 12 is the identical P1 and P2 sites of Inhibitor 65.(1996)<ref> M. R. Wiley, N. Y. Chirgadze, D. K. Clawson, T. J. Craft, D. S. GiffordMoore, N. D. Jones, J. L. Olkowski, L. C. Weir, G. F. Smith, Bioorg. Med. Chem. Lett. 1996, 6, 2387. http://www.sciencedirect.com/science/article/pii/0960894X96004428 </ref>]]
Its selectivity was gained by binding its nitrogens on the benzamidine <scene name='Sean_Swale/Human_Thrombin_Inhibitor/P1_residue/1'>group</scene> by hydrogen bonding to Asp 189, and by fitting its benzamidine benzene into a hydrophobic pocket with Ser 214-Glu 217 and Asp 189-Glu 192 on the other side. The <scene name='Sean_Swale/Human_Thrombin_Inhibitor/P2_proline/1'>proline</scene> residue is in another hydrophobic pocket made up of His 57, Tyr 60A, Leu 99, and Trp 60D. The rest of this structure is unimportant on review of inhibitor 65 because only the amidinobenzylamine which occupies R1 and the proline which occupies the R2 sit are the same residues on inhibitor 65.<ref> M. R. Wiley, N. Y. Chirgadze, D. K. Clawson, T. J. Craft, D. S. GiffordMoore, N. D. Jones, J. L. Olkowski, L. C. Weir, G. F. Smith, Bioorg. Med. Chem. Lett. 1996, 6, 2387. http://www.sciencedirect.com/science/article/pii/0960894X96004428 </ref>

----

===P3 and P4 of Inhibitor 65===
[[Image:Inhibitor 65.png|center|200px|frame|<ref> DOI: 10.1002/cmdc.201200292</ref> ]]
Inhibitor 65 additionally has a <scene name='Sean_Swale/Human_Thrombin_Inhibitor/P4/1'>P4</scene> sulfonyl group with a methoxy group at the end of the residue. The residue sits in a hydrophobic <scene name='Sean_Swale/Human_Thrombin_Inhibitor/P4_binding_pocket/1'>pocket</scene>. It sits in tight VanderWaals structure with the surrounding residues Leu 99, Tyr 60A, Arg 97, Glu 97, and Asn 98.The <scene name='Sean_Swale/Human_Thrombin_Inhibitor/P4_sulfonyl/1'>sulfonyl</scene> group holds its own VanderWaal forces. Additionally, the <scene name='Sean_Swale/Human_Thrombin_Inhibitor/P4_chlorine/1'>chlorine</scene> points to the carbonyl oxygen of Asn 98 and there is a weak Cl-π bond with Trp 215. For the P3 <scene name='Sean_Swale/Human_Thrombin_Inhibitor/P3_binding_site/6'>residue</scene>, there the backbone of asparagine forms and anti parallel beta sheet with Gly 216. The alkylated asparagine’s NH binds to a water molecule which then connects to Glu 192, and the hydrogens of Gly 219 and Gly 216.
[[Image:Thrombin1.gif|left|frame|200px|a) Stereo view of the complete inhibitor structure provided with its electron density in the active site of thrombin. Thrombin is shown with its solvent- accessible surface. b) The P4 sulfonyl residue is located in the aryl binding pocket. The chlorine atom points to the carbonyl oxygen of Asn 98 and accommodates a position above the indole moiety of Trp 215. The methoxy group perfectly fills the upper niche of the S3/4 pocket. c) The P3 side chain is directed into the solvent, where its amide NH binds via a bridging water molecule to Glu 192, Gly 216 and Gly 219.<ref> DOI: 10.1002/cmdc.201200292</ref> ]]

</StructureSection>
This is the <scene name='Sean_Swale/Human_Thrombin_Inhibitor/Thrombin_active_site/2'>active site</scene> of thrombin

[[Image:1ppb-transparent.gif|right|500px|frame|Thrombin with serine residue visible.<ref>January 2002 Molecule of the Month by David Goodsell http://www.rcsb.org/pdb/101/motm.do?momID=25 </ref>]]

==References==
{{reflist}}

Sean Swale/Human Thrombin Inhibitor

2012-11-16T20:17:01Z

Sean Swale:

<StructureSection load='3utu' size='500' frame='false' align='right' |caption='Human Thrombin' scene=''>

===Reasons to develop another <scene name='Sean_Swale/Human_Thrombin_Inhibitor/Active_site/3'>Thrombin</scene> Inhibitor===
Thrombin is a serine protease that cleaves fibrinogen to allow fibrin to form stringy networks that trap red blood cells to form clots. Thrombin is a serine protease because it cleaves fibrinogen with its serine residue. Thrombin when made by the body is tethered to blood vessels so that it cannot cause clots throughout the body causing strokes and heart attacks. Additionally, thrombin is only activated for a few seconds to limit the clotted area to the injured area<ref>January 2002 Molecule of the Month by David Goodsell http://www.rcsb.org/pdb/101/motm.do?momID=25 </ref>. However, when fibrin has accumulated at an injury site, sometimes it will break away and occlude a blood vessel which can cause stroke or heart attack. In order to prevent venous thrombosis, blood clots, after surgery or during dialysis when blood is in contact with artificial devices, Heparin is normally administered. Unfortunately Heparin is neutralized by plasma proteins in the blood, is less efficient for the inhibition of clot bound thrombin, and can trigger an enormous immune response. Antithrombotic drugs like Hirudin will be given if Heparin is not able to be tolerated or if the person receives regular dialysis. Hirudin administration require large doses to maintain proper inhibition of Thrombin which heavily taxes the body. Chemists have been working on designer drugs to increase selectivity and potency. One compound which has shown great selectivity and potency in vitro is <scene name='Sean_Swale/Human_Thrombin_Inhibitor/Inhibitor_65/1'>inhibitor 65</scene>.<ref> DOI: 10.1002/cmdc.201200292</ref>

----

===Phe-Pro-p-amidinobenzylamine===
An early experiment to find a better thrombin inhibitor yielded a structure that was able to bond to the P1 and P2 sites of Thrombin effectively. In 1996 Lilly research laboratories created D-Phe-Pro-p-amidinobenzylamine by making improvements on the previous structure D-Phe-Pro-Agmatine. The new compound they created bonded to thrombin 130x more than it did to trypsin (also a serine protease), and it was highly selective of thrombin over fibrinolytic enzymes which break down fibrin clots. The inhibitor bound with Thrombin at rates 26,000x greater than with plasmin,<ref> http://voices.yahoo.com/what-fibrinolytic-enzymes-6186058.html?cat=68</ref>, 170,000x greater than with t-Pa, and 400,000x greater than with urokinase.
[[Image:1996 inhibitor rates.png|left|50|frame|Inhibitor 12 is the identical P1 and P2 sites of Inhibitor 65.(1996)<ref> M. R. Wiley, N. Y. Chirgadze, D. K. Clawson, T. J. Craft, D. S. GiffordMoore, N. D. Jones, J. L. Olkowski, L. C. Weir, G. F. Smith, Bioorg. Med. Chem. Lett. 1996, 6, 2387. http://www.sciencedirect.com/science/article/pii/0960894X96004428 </ref>]]
Its selectivity was gained by binding its nitrogens on the benzamidine <scene name='Sean_Swale/Human_Thrombin_Inhibitor/P1_residue/1'>group</scene> by hydrogen bonding to Asp 189, and by fitting its benzamidine benzene into a hydrophobic pocket with Ser 214-Glu 217 and Asp 189-Glu 192 on the other side. The <scene name='Sean_Swale/Human_Thrombin_Inhibitor/P2_proline/1'>proline</scene> residue is in another hydrophobic pocket made up of His 57, Tyr 60A, Leu 99, and Trp 60D. The rest of this structure is unimportant on review of inhibitor 65 because only the amidinobenzylamine which occupies R1 and the proline which occupies the R2 sit are the same residues on inhibitor 65.<ref> M. R. Wiley, N. Y. Chirgadze, D. K. Clawson, T. J. Craft, D. S. GiffordMoore, N. D. Jones, J. L. Olkowski, L. C. Weir, G. F. Smith, Bioorg. Med. Chem. Lett. 1996, 6, 2387. http://www.sciencedirect.com/science/article/pii/0960894X96004428 </ref>

----

===P3 and P4 of Inhibitor 65===
[[Image:Inhibitor 65.png|center|200px|frame|<ref> DOI: 10.1002/cmdc.201200292</ref> ]]
Inhibitor 65 additionally has a <scene name='Sean_Swale/Human_Thrombin_Inhibitor/P4/1'>P4</scene> sulfonyl group with a methoxy group at the end of the residue. The residue sits in a hydrophobic <scene name='Sean_Swale/Human_Thrombin_Inhibitor/P4_binding_pocket/1'>pocket</scene>. It sits in tight VanderWaals structure with the surrounding residues Leu 99, Tyr 60A, Arg 97, Glu 97, and Asn 98.The <scene name='Sean_Swale/Human_Thrombin_Inhibitor/P4_sulfonyl/1'>sulfonyl</scene> group holds its own VanderWaal forces. Additionally, the <scene name='Sean_Swale/Human_Thrombin_Inhibitor/P4_chlorine/1'>chlorine</scene> points to the carbonyl oxygen of Asn 98 and there is a weak Cl-π bond with Trp 215. For the P3 <scene name='Sean_Swale/Human_Thrombin_Inhibitor/P3_binding_site/6'>residue</scene>, there the backbone of asparagine forms and anti parallel beta sheet with Gly 216. The alkylated asparagine’s NH binds to a water molecule which then connects to Glu 192, and the hydrogens of Gly 219 and Gly 216.
[[Image:Thrombin1.gif|left|frame|200px|a) Stereo view of the complete inhibitor structure provided with its electron density in the active site of thrombin. Thrombin is shown with its solvent- accessible surface. b) The P4 sulfonyl residue is located in the aryl binding pocket. The chlorine atom points to the carbonyl oxygen of Asn 98 and accommodates a position above the indole moiety of Trp 215. The methoxy group perfectly fills the upper niche of the S3/4 pocket. c) The P3 side chain is directed into the solvent, where its amide NH binds via a bridging water molecule to Glu 192, Gly 216 and Gly 219.<ref> DOI: 10.1002/cmdc.201200292</ref> ]]

</StructureSection>
This is the <scene name='Sean_Swale/Human_Thrombin_Inhibitor/Thrombin_active_site/2'>active site</scene> of thrombin

[[Image:1ppb-transparent.gif|right|500px|frame|Thrombin with serine residue visible.<ref>January 2002 Molecule of the Month by David Goodsell http://www.rcsb.org/pdb/101/motm.do?momID=25 </ref>]]

==References==
{{reflist}}

Sean Swale/Human Thrombin Inhibitor

2012-11-16T20:15:50Z

Sean Swale:

<StructureSection load='3utu' size='500' frame='false' align='right' |caption='Human Thrombin' scene=''>

===Reasons to develop another <scene name='Sean_Swale/Human_Thrombin_Inhibitor/Active_site/3'>Thrombin</scene> Inhibitor===
Thrombin is a serine protease that cleaves fibrinogen to allow fibrin to form stringy networks that trap red blood cells to form clots. Thrombin is a serine protease because it cleaves fibrinogen with its serine residue. Thrombin when made by the body is tethered to blood vessels so that it cannot cause clots throughout the body causing strokes and heart attacks. Additionally, thrombin is only activated for a few seconds to limit the clotted area to the injured area<ref>January 2002 Molecule of the Month by David Goodsell http://www.rcsb.org/pdb/101/motm.do?momID=25 </ref>. However, when fibrin has accumulated at an injury site, sometimes it will break away and occlude a blood vessel which can cause stroke or heart attack. In order to prevent venous thrombosis, blood clots, after surgery or during dialysis when blood is in contact with artificial devices, Heparin is normally administered. Unfortunately Heparin is neutralized by plasma proteins in the blood, is less efficient for the inhibition of clot bound thrombin, and can trigger an enormous immune response. Antithrombotic drugs like Hirudin will be given if Heparin is not able to be tolerated or if the person receives regular dialysis. Hirudin administration require large doses to maintain proper inhibition of Thrombin which heavily taxes the body. Chemists have been working on designer drugs to increase selectivity and potency. One compound which has shown great selectivity and potency in vitro is <scene name='Sean_Swale/Human_Thrombin_Inhibitor/Inhibitor_65/1'>inhibitor 65</scene>.<ref> DOI: 10.1002/cmdc.201200292</ref>

----

===Phe-Pro-p-amidinobenzylamine===
An early experiment to find a better thrombin inhibitor yielded a structure that was able to bond to the P1 and P2 sites of Thrombin effectively. In 1996 Lilly research laboratories created D-Phe-Pro-p-amidinobenzylamine by making improvements on the previous structure D-Phe-Pro-Agmatine. The new compound they created bonded to thrombin 130x more than it did to trypsin (also a serine protease), and it was highly selective of thrombin over fibrinolytic enzymes which break down fibrin clots. The inhibitor bound with Thrombin at rates 26,000x greater than with plasmin,<ref> http://voices.yahoo.com/what-fibrinolytic-enzymes-6186058.html?cat=68</ref>, 170,000x greater than with t-Pa, and 400,000x greater than with urokinase.
[[Image:1996 inhibitor rates.png|left|100|frame|Inhibitor 12 is the identical P1 and P2 sites of Inhibitor 65.(1996)<ref> M. R. Wiley, N. Y. Chirgadze, D. K. Clawson, T. J. Craft, D. S. GiffordMoore, N. D. Jones, J. L. Olkowski, L. C. Weir, G. F. Smith, Bioorg. Med. Chem. Lett. 1996, 6, 2387. http://www.sciencedirect.com/science/article/pii/0960894X96004428 </ref>]]
Its selectivity was gained by binding its nitrogens on the benzamidine <scene name='Sean_Swale/Human_Thrombin_Inhibitor/P1_residue/1'>group</scene> by hydrogen bonding to Asp 189, and by fitting its benzamidine benzene into a hydrophobic pocket with Ser 214-Glu 217 and Asp 189-Glu 192 on the other side. The <scene name='Sean_Swale/Human_Thrombin_Inhibitor/P2_proline/1'>proline</scene> residue is in another hydrophobic pocket made up of His 57, Tyr 60A, Leu 99, and Trp 60D. The rest of this structure is unimportant on review of inhibitor 65 because only the amidinobenzylamine which occupies R1 and the proline which occupies the R2 sit are the same residues on inhibitor 65.<ref> M. R. Wiley, N. Y. Chirgadze, D. K. Clawson, T. J. Craft, D. S. GiffordMoore, N. D. Jones, J. L. Olkowski, L. C. Weir, G. F. Smith, Bioorg. Med. Chem. Lett. 1996, 6, 2387. http://www.sciencedirect.com/science/article/pii/0960894X96004428 </ref>

----

===P3 and P4 of Inhibitor 65===
[[Image:Inhibitor 65.png|center|200px|frame|<ref> DOI: 10.1002/cmdc.201200292</ref> ]]
Inhibitor 65 additionally has a <scene name='Sean_Swale/Human_Thrombin_Inhibitor/P4/1'>P4</scene> sulfonyl group with a methoxy group at the end of the residue. The residue sits in a hydrophobic <scene name='Sean_Swale/Human_Thrombin_Inhibitor/P4_binding_pocket/1'>pocket</scene>. It sits in tight VanderWaals structure with the surrounding residues Leu 99, Tyr 60A, Arg 97, Glu 97, and Asn 98.The <scene name='Sean_Swale/Human_Thrombin_Inhibitor/P4_sulfonyl/1'>sulfonyl</scene> group holds its own VanderWaal forces. Additionally, the <scene name='Sean_Swale/Human_Thrombin_Inhibitor/P4_chlorine/1'>chlorine</scene> points to the carbonyl oxygen of Asn 98 and there is a weak Cl-π bond with Trp 215. For the P3 <scene name='Sean_Swale/Human_Thrombin_Inhibitor/P3_binding_site/6'>residue</scene>, there the backbone of asparagine forms and anti parallel beta sheet with Gly 216. The alkylated asparagine’s NH binds to a water molecule which then connects to Glu 192, and the hydrogens of Gly 219 and Gly 216.
[[Image:Thrombin1.gif|left|frame|200px|a) Stereo view of the complete inhibitor structure provided with its electron density in the active site of thrombin. Thrombin is shown with its solvent- accessible surface. b) The P4 sulfonyl residue is located in the aryl binding pocket. The chlorine atom points to the carbonyl oxygen of Asn 98 and accommodates a position above the indole moiety of Trp 215. The methoxy group perfectly fills the upper niche of the S3/4 pocket. c) The P3 side chain is directed into the solvent, where its amide NH binds via a bridging water molecule to Glu 192, Gly 216 and Gly 219.<ref> DOI: 10.1002/cmdc.201200292</ref> ]]

</StructureSection>
This is the <scene name='Sean_Swale/Human_Thrombin_Inhibitor/Thrombin_active_site/2'>active site</scene> of thrombin

[[Image:1ppb-transparent.gif|right|500px|frame|Thrombin with serine residue visible.<ref>January 2002 Molecule of the Month by David Goodsell http://www.rcsb.org/pdb/101/motm.do?momID=25 </ref>]]

==References==
{{reflist}}

Sean Swale/Human Thrombin Inhibitor

2012-11-16T20:12:20Z

Sean Swale:

<StructureSection load='3utu' size='500' frame='false' align='right' |caption='Human Thrombin' scene=''>

===Reasons to develop another <scene name='Sean_Swale/Human_Thrombin_Inhibitor/Active_site/3'>Thrombin</scene> Inhibitor===
Thrombin is a serine protease that cleaves fibrinogen to allow fibrin to form stringy networks that trap red blood cells to form clots. Thrombin is a serine protease because it cleaves fibrinogen with its serine residue. Thrombin when made by the body is tethered to blood vessels so that it cannot cause clots throughout the body causing strokes and heart attacks. Additionally, thrombin is only activated for a few seconds to limit the clotted area to the injured area<ref>January 2002 Molecule of the Month by David Goodsell http://www.rcsb.org/pdb/101/motm.do?momID=25 </ref>. However, when fibrin has accumulated at an injury site, sometimes it will break away and occlude a blood vessel which can cause stroke or heart attack. In order to prevent venous thrombosis, blood clots, after surgery or during dialysis when blood is in contact with artificial devices, Heparin is normally administered. Unfortunately Heparin is neutralized by plasma proteins in the blood, is less efficient for the inhibition of clot bound thrombin, and can trigger an enormous immune response. Antithrombotic drugs like Hirudin will be given if Heparin is not able to be tolerated or if the person receives regular dialysis. Hirudin administration require large doses to maintain proper inhibition of Thrombin which heavily taxes the body. Chemists have been working on designer drugs to increase selectivity and potency. One compound which has shown great selectivity and potency in vitro is <scene name='Sean_Swale/Human_Thrombin_Inhibitor/Inhibitor_65/1'>inhibitor 65</scene>.<ref> DOI: 10.1002/cmdc.201200292</ref>

----

===Phe-Pro-p-amidinobenzylamine===
An early experiment to find a better thrombin inhibitor yielded a structure that was able to bond to the P1 and P2 sites of Thrombin effectively. In 1996 Lilly research laboratories created D-Phe-Pro-p-amidinobenzylamine by making improvements on the previous structure D-Phe-Pro-Agmatine. The new compound they created bonded to thrombin 130x more than it did to trypsin (also a serine protease), and it was highly selective of thrombin over fibrinolytic enzymes which break down fibrin clots. The inhibitor bound with Thrombin at rates 26,000x greater than with plasmin,<ref> http://voices.yahoo.com/what-fibrinolytic-enzymes-6186058.html?cat=68</ref>, 170,000x greater than with t-Pa, and 400,000x greater than with urokinase.
[[Image:1996 inhibitor rates.png|left|100px|frame|Inhibitor 12 is the identical P1 and P2 sites of Inhibitor 65.(1996)<ref> M. R. Wiley, N. Y. Chirgadze, D. K. Clawson, T. J. Craft, D. S. GiffordMoore, N. D. Jones, J. L. Olkowski, L. C. Weir, G. F. Smith, Bioorg. Med. Chem. Lett. 1996, 6, 2387. http://www.sciencedirect.com/science/article/pii/0960894X96004428 </ref>]]
Its selectivity was gained by binding its nitrogens on the benzamidine <scene name='Sean_Swale/Human_Thrombin_Inhibitor/P1_residue/1'>group</scene> by hydrogen bonding to Asp 189, and by fitting its benzamidine benzene into a hydrophobic pocket with Ser 214-Glu 217 and Asp 189-Glu 192 on the other side. The <scene name='Sean_Swale/Human_Thrombin_Inhibitor/P2_proline/1'>proline</scene> residue is in another hydrophobic pocket made up of His 57, Tyr 60A, Leu 99, and Trp 60D. The rest of this structure is unimportant on review of inhibitor 65 because only the amidinobenzylamine which occupies R1 and the proline which occupies the R2 sit are the same residues on inhibitor 65.<ref> M. R. Wiley, N. Y. Chirgadze, D. K. Clawson, T. J. Craft, D. S. GiffordMoore, N. D. Jones, J. L. Olkowski, L. C. Weir, G. F. Smith, Bioorg. Med. Chem. Lett. 1996, 6, 2387. http://www.sciencedirect.com/science/article/pii/0960894X96004428 </ref>

----

===P3 and P4 of Inhibitor 65===
[[Image:Inhibitor 65.png|center|200px|frame|<ref> DOI: 10.1002/cmdc.201200292</ref> ]]
Inhibitor 65 additionally has a <scene name='Sean_Swale/Human_Thrombin_Inhibitor/P4/1'>P4</scene> sulfonyl group with a methoxy group at the end of the residue. The residue sits in a hydrophobic <scene name='Sean_Swale/Human_Thrombin_Inhibitor/P4_binding_pocket/1'>pocket</scene>. It sits in tight VanderWaals structure with the surrounding residues Leu 99, Tyr 60A, Arg 97, Glu 97, and Asn 98.The <scene name='Sean_Swale/Human_Thrombin_Inhibitor/P4_sulfonyl/1'>sulfonyl</scene> group holds its own VanderWaal forces. Additionally, the <scene name='Sean_Swale/Human_Thrombin_Inhibitor/P4_chlorine/1'>chlorine</scene> points to the carbonyl oxygen of Asn 98 and there is a weak Cl-π bond with Trp 215. For the P3 <scene name='Sean_Swale/Human_Thrombin_Inhibitor/P3_binding_site/6'>residue</scene>, there the backbone of asparagine forms and anti parallel beta sheet with Gly 216. The alkylated asparagine’s NH binds to a water molecule which then connects to Glu 192, and the hydrogens of Gly 219 and Gly 216.
[[Image:Thrombin1.gif|left|frame|200px|a) Stereo view of the complete inhibitor structure provided with its electron density in the active site of thrombin. Thrombin is shown with its solvent- accessible surface. b) The P4 sulfonyl residue is located in the aryl binding pocket. The chlorine atom points to the carbonyl oxygen of Asn 98 and accommodates a position above the indole moiety of Trp 215. The methoxy group perfectly fills the upper niche of the S3/4 pocket. c) The P3 side chain is directed into the solvent, where its amide NH binds via a bridging water molecule to Glu 192, Gly 216 and Gly 219.<ref> DOI: 10.1002/cmdc.201200292</ref> ]]

</StructureSection>
This is the <scene name='Sean_Swale/Human_Thrombin_Inhibitor/Thrombin_active_site/2'>active site</scene> of thrombin

[[Image:1ppb-transparent.gif|right|500px|frame|Thrombin with serine residue visible.<ref>January 2002 Molecule of the Month by David Goodsell http://www.rcsb.org/pdb/101/motm.do?momID=25 </ref>]]

==References==
{{reflist}}

Sean Swale/Human Thrombin Inhibitor

2012-11-16T01:08:16Z

Sean Swale:

<StructureSection load='3utu' size='500' frame='false' align='right' |caption='Human Thrombin' scene=''>

===Reasons to develop another <scene name='Sean_Swale/Human_Thrombin_Inhibitor/Active_site/3'>Thrombin</scene> Inhibitor===
Thrombin is a serine protease that cleaves fibrinogen to allow fibrin to form stringy networks that trap red blood cells to form clots. Thrombin is a serine protease because it cleaves fibrinogen with its serine residue. Thrombin when made by the body is tethered to blood vessels so that it cannot cause clots throughout the body causing strokes and heart attacks. Additionally, thrombin is only activated for a few seconds to limit the clotted area to the injured area<ref>January 2002 Molecule of the Month by David Goodsell http://www.rcsb.org/pdb/101/motm.do?momID=25 </ref>. However, when fibrin has accumulated at an injury site, sometimes it will break away and occlude a blood vessel which can cause stroke or heart attack. In order to prevent venous thrombosis, blood clots, after surgery or during dialysis when blood is in contact with artificial devices, Heparin is normally administered. Unfortunately Heparin is neutralized by plasma proteins in the blood, is less efficient for the inhibition of clot bound thrombin, and can trigger an enormous immune response. Antithrombotic drugs like Hirudin will be given if Heparin is not able to be tolerated or if the person receives regular dialysis. Hirudin administration require large doses to maintain proper inhibition of Thrombin which heavily taxes the body. Chemists have been working on designer drugs to increase selectivity and potency. One compound which has shown great selectivity and potency in vitro is <scene name='Sean_Swale/Human_Thrombin_Inhibitor/Inhibitor_65/1'>inhibitor 65</scene>.<ref> DOI: 10.1002/cmdc.201200292</ref>

----

===Phe-Pro-p-amidinobenzylamine===
An early experiment to find a better thrombin inhibitor yielded a structure that was able to bond to the P1 and P2 sites of Thrombin effectively. In 1996 Lilly research laboratories created D-Phe-Pro-p-amidinobenzylamine by making improvements on the previous structure D-Phe-Pro-Agmatine. The new compound they created bonded to thrombin 130x more than it did to trypsin (also a serine protease), and it was highly selective of thrombin over fibrinolytic enzymes which break down fibrin clots. The inhibitor bound with Thrombin at rates 26,000x greater than with plasmin,<ref> http://voices.yahoo.com/what-fibrinolytic-enzymes-6186058.html?cat=68</ref>, 170,000x greater than with t-Pa, and 400,000x greater than with urokinase.
[[Image:1996 inhibitor rates.png|center|100px|frame|Inhibitor 12 is the identical P1 and P2 sites of Inhibitor 65.(1996)<ref> M. R. Wiley, N. Y. Chirgadze, D. K. Clawson, T. J. Craft, D. S. GiffordMoore, N. D. Jones, J. L. Olkowski, L. C. Weir, G. F. Smith, Bioorg. Med. Chem. Lett. 1996, 6, 2387. http://www.sciencedirect.com/science/article/pii/0960894X96004428 </ref>]]
Its selectivity was gained by binding its nitrogens on the benzamidine <scene name='Sean_Swale/Human_Thrombin_Inhibitor/P1_residue/1'>group</scene> by hydrogen bonding to Asp 189, and by fitting its benzamidine benzene into a hydrophobic pocket with Ser 214-Glu 217 and Asp 189-Glu 192 on the other side. The <scene name='Sean_Swale/Human_Thrombin_Inhibitor/P2_proline/1'>proline</scene> residue is in another hydrophobic pocket made up of His 57, Tyr 60A, Leu 99, and Trp 60D. The rest of this structure is unimportant on review of inhibitor 65 because only the amidinobenzylamine which occupies R1 and the proline which occupies the R2 sit are the same residues on inhibitor 65.<ref> M. R. Wiley, N. Y. Chirgadze, D. K. Clawson, T. J. Craft, D. S. GiffordMoore, N. D. Jones, J. L. Olkowski, L. C. Weir, G. F. Smith, Bioorg. Med. Chem. Lett. 1996, 6, 2387. http://www.sciencedirect.com/science/article/pii/0960894X96004428 </ref>

----

===P3 and P4 of Inhibitor 65===
[[Image:Inhibitor 65.png|center|200px|frame|<ref> DOI: 10.1002/cmdc.201200292</ref> ]]
Inhibitor 65 additionally has a <scene name='Sean_Swale/Human_Thrombin_Inhibitor/P4/1'>P4</scene> sulfonyl group with a methoxy group at the end of the residue. The residue sits in a hydrophobic <scene name='Sean_Swale/Human_Thrombin_Inhibitor/P4_binding_pocket/1'>pocket</scene>. It sits in tight VanderWaals structure with the surrounding residues Leu 99, Tyr 60A, Arg 97, Glu 97, and Asn 98.The <scene name='Sean_Swale/Human_Thrombin_Inhibitor/P4_sulfonyl/1'>sulfonyl</scene> group holds its own VanderWaal forces. Additionally, the <scene name='Sean_Swale/Human_Thrombin_Inhibitor/P4_chlorine/1'>chlorine</scene> points to the carbonyl oxygen of Asn 98 and there is a weak Cl-π bond with Trp 215. For the P3 <scene name='Sean_Swale/Human_Thrombin_Inhibitor/P3_binding_site/6'>residue</scene>, there the backbone of asparagine forms and anti parallel beta sheet with Gly 216. The alkylated asparagine’s NH binds to a water molecule which then connects to Glu 192, and the hydrogens of Gly 219 and Gly 216.
[[Image:Thrombin1.gif|left|frame|300px|a) Stereo view of the complete inhibitor structure provided with its electron density in the active site of thrombin. Thrombin is shown with its solvent- accessible surface. b) The P4 sulfonyl residue is located in the aryl binding pocket. The chlorine atom points to the carbonyl oxygen of Asn 98 and accommodates a position above the indole moiety of Trp 215. The methoxy group perfectly fills the upper niche of the S3/4 pocket. c) The P3 side chain is directed into the solvent, where its amide NH binds via a bridging water molecule to Glu 192, Gly 216 and Gly 219.<ref> DOI: 10.1002/cmdc.201200292</ref> ]]

</StructureSection>
This is the <scene name='Sean_Swale/Human_Thrombin_Inhibitor/Thrombin_active_site/2'>active site</scene> of thrombin

[[Image:1ppb-transparent.gif|right|500px|frame|Thrombin with serine residue visible.<ref>January 2002 Molecule of the Month by David Goodsell http://www.rcsb.org/pdb/101/motm.do?momID=25 </ref>]]

==References==
{{reflist}}

Sean Swale/Human Thrombin Inhibitor

2012-11-16T01:07:05Z

Sean Swale:

<StructureSection load='3utu' size='500' frame='false' align='right' |caption='Human Thrombin' scene=''>

===Reasons to develop another <scene name='Sean_Swale/Human_Thrombin_Inhibitor/Active_site/3'>Thrombin</scene> Inhibitor===
Thrombin is a serine protease that cleaves fibrinogen to allow fibrin to form stringy networks that trap red blood cells to form clots. Thrombin is a serine protease because it cleaves fibrinogen with its serine residue. Thrombin when made by the body is tethered to blood vessels so that it cannot cause clots throughout the body causing strokes and heart attacks. Additionally, thrombin is only activated for a few seconds to limit the clotted area to the injured area<ref>January 2002 Molecule of the Month by David Goodsell http://www.rcsb.org/pdb/101/motm.do?momID=25 </ref>. However, when fibrin has accumulated at an injury site, sometimes it will break away and occlude a blood vessel which can cause stroke or heart attack. In order to prevent venous thrombosis, blood clots, after surgery or during dialysis when blood is in contact with artificial devices, Heparin is normally administered. Unfortunately Heparin is neutralized by plasma proteins in the blood, is less efficient for the inhibition of clot bound thrombin, and can trigger an enormous immune response. Antithrombotic drugs like Hirudin will be given if Heparin is not able to be tolerated or if the person receives regular dialysis. Hirudin administration require large doses to maintain proper inhibition of Thrombin which heavily taxes the body. Chemists have been working on designer drugs to increase selectivity and potency. One compound which has shown great selectivity and potency in vitro is <scene name='Sean_Swale/Human_Thrombin_Inhibitor/Inhibitor_65/1'>inhibitor 65</scene>.<ref> DOI: 10.1002/cmdc.201200292</ref>

----

===Phe-Pro-p-amidinobenzylamine===
An early experiment to find a better thrombin inhibitor yielded a structure that was able to bond to the P1 and P2 sites of Thrombin effectively. In 1996 Lilly research laboratories created D-Phe-Pro-p-amidinobenzylamine by making improvements on the previous structure D-Phe-Pro-Agmatine. The new compound they created bonded to thrombin 130x more than it did to trypsin (also a serine protease), and it was highly selective of thrombin over fibrinolytic enzymes which break down fibrin clots. The inhibitor bound with Thrombin at rates 26,000x greater than with plasmin,<ref> http://voices.yahoo.com/what-fibrinolytic-enzymes-6186058.html?cat=68</ref>, 170,000x greater than with t-Pa, and 400,000x greater than with urokinase.
[[Image:1996 inhibitor rates.png|center|300px|frame|Inhibitor 12 is the identical P1 and P2 sites of Inhibitor 65.(1996)<ref> M. R. Wiley, N. Y. Chirgadze, D. K. Clawson, T. J. Craft, D. S. GiffordMoore, N. D. Jones, J. L. Olkowski, L. C. Weir, G. F. Smith, Bioorg. Med. Chem. Lett. 1996, 6, 2387. http://www.sciencedirect.com/science/article/pii/0960894X96004428 </ref>]]
Its selectivity was gained by binding its nitrogens on the benzamidine <scene name='Sean_Swale/Human_Thrombin_Inhibitor/P1_residue/1'>group</scene> by hydrogen bonding to Asp 189, and by fitting its benzamidine benzene into a hydrophobic pocket with Ser 214-Glu 217 and Asp 189-Glu 192 on the other side. The <scene name='Sean_Swale/Human_Thrombin_Inhibitor/P2_proline/1'>proline</scene> residue is in another hydrophobic pocket made up of His 57, Tyr 60A, Leu 99, and Trp 60D. The rest of this structure is unimportant on review of inhibitor 65 because only the amidinobenzylamine which occupies R1 and the proline which occupies the R2 sit are the same residues on inhibitor 65.<ref> M. R. Wiley, N. Y. Chirgadze, D. K. Clawson, T. J. Craft, D. S. GiffordMoore, N. D. Jones, J. L. Olkowski, L. C. Weir, G. F. Smith, Bioorg. Med. Chem. Lett. 1996, 6, 2387. http://www.sciencedirect.com/science/article/pii/0960894X96004428 </ref>

----

===P3 and P4 of Inhibitor 65===
[[Image:Inhibitor 65.png|center|400px|frame|<ref> DOI: 10.1002/cmdc.201200292</ref> ]]
Inhibitor 65 additionally has a <scene name='Sean_Swale/Human_Thrombin_Inhibitor/P4/1'>P4</scene> sulfonyl group with a methoxy group at the end of the residue. The residue sits in a hydrophobic <scene name='Sean_Swale/Human_Thrombin_Inhibitor/P4_binding_pocket/1'>pocket</scene>. It sits in tight VanderWaals structure with the surrounding residues Leu 99, Tyr 60A, Arg 97, Glu 97, and Asn 98.The <scene name='Sean_Swale/Human_Thrombin_Inhibitor/P4_sulfonyl/1'>sulfonyl</scene> group holds its own VanderWaal forces. Additionally, the <scene name='Sean_Swale/Human_Thrombin_Inhibitor/P4_chlorine/1'>chlorine</scene> points to the carbonyl oxygen of Asn 98 and there is a weak Cl-π bond with Trp 215. For the P3 <scene name='Sean_Swale/Human_Thrombin_Inhibitor/P3_binding_site/6'>residue</scene>, there the backbone of asparagine forms and anti parallel beta sheet with Gly 216. The alkylated asparagine’s NH binds to a water molecule which then connects to Glu 192, and the hydrogens of Gly 219 and Gly 216.
[[Image:Thrombin1.gif|left|frame|300px|a) Stereo view of the complete inhibitor structure provided with its electron density in the active site of thrombin. Thrombin is shown with its solvent- accessible surface. b) The P4 sulfonyl residue is located in the aryl binding pocket. The chlorine atom points to the carbonyl oxygen of Asn 98 and accommodates a position above the indole moiety of Trp 215. The methoxy group perfectly fills the upper niche of the S3/4 pocket. c) The P3 side chain is directed into the solvent, where its amide NH binds via a bridging water molecule to Glu 192, Gly 216 and Gly 219.<ref> DOI: 10.1002/cmdc.201200292</ref> ]]

</StructureSection>
This is the <scene name='Sean_Swale/Human_Thrombin_Inhibitor/Thrombin_active_site/2'>active site</scene> of thrombin

[[Image:1ppb-transparent.gif|right|500px|frame|Thrombin with serine residue visible.<ref>January 2002 Molecule of the Month by David Goodsell http://www.rcsb.org/pdb/101/motm.do?momID=25 </ref>]]

==References==
{{reflist}}

Sean Swale/Human Thrombin Inhibitor

2012-11-16T00:01:22Z

Sean Swale:

<StructureSection load='3utu' size='500' frame='false' align='right' |caption='Human Thrombin' scene=''>

===Reasons to develop another <scene name='Sean_Swale/Human_Thrombin_Inhibitor/Active_site/3'>Thrombin</scene> Inhibitor===
Thrombin is a serine protease that cleaves fibrinogen to allow fibrin to form stringy networks that trap red blood cells to form clots. Thrombin is a serine protease because it cleaves fibrinogen with its serine residue. Thrombin when made by the body is tethered to blood vessels so that it cannot cause clots throughout the body causing strokes and heart attacks. Additionally, thrombin is only activated for a few seconds to limit the clotted area to the injured area<ref>January 2002 Molecule of the Month by David Goodsell http://www.rcsb.org/pdb/101/motm.do?momID=25 </ref>. However, when fibrin has accumulated at an injury site, sometimes it will break away and occlude a blood vessel which can cause stroke or heart attack. In order to prevent venous thrombosis, blood clots, after surgery or during dialysis when blood is in contact with artificial devices, Heparin is normally administered. Unfortunately Heparin is neutralized by plasma proteins in the blood, is less efficient for the inhibition of clot bound thrombin, and can trigger an enormous immune response. Antithrombotic drugs like Hirudin will be given if Heparin is not able to be tolerated or if the person receives regular dialysis. Hirudin administration require large doses to maintain proper inhibition of Thrombin which heavily taxes the body. Chemists have been working on designer drugs to increase selectivity and potency. One compound which has shown great selectivity and potency in vitro is <scene name='Sean_Swale/Human_Thrombin_Inhibitor/Inhibitor_65/1'>inhibitor 65</scene>.<ref> DOI: 10.1002/cmdc.201200292</ref>

----

===Phe-Pro-p-amidinobenzylamine===
An early experiment to find a better thrombin inhibitor yielded a structure that was able to bond to the P1 and P2 sites of Thrombin effectively. In 1996 Lilly research laboratories created D-Phe-Pro-p-amidinobenzylamine by making improvements on the previous structure D-Phe-Pro-Agmatine. The new compound they created bonded to thrombin 130x more than it did to trypsin (also a serine protease), and it was highly selective of thrombin over fibrinolytic enzymes which break down fibrin clots. The inhibitor bound with Thrombin at rates 26,000x greater than with plasmin,<ref> http://voices.yahoo.com/what-fibrinolytic-enzymes-6186058.html?cat=68</ref>, 170,000x greater than with t-Pa, and 400,000x greater than with urokinase.
[[Image:1996 inhibitor rates.png|center|600px|frame|Inhibitor 12 is the identical P1 and P2 sites of Inhibitor 65.(1996)<ref> M. R. Wiley, N. Y. Chirgadze, D. K. Clawson, T. J. Craft, D. S. GiffordMoore, N. D. Jones, J. L. Olkowski, L. C. Weir, G. F. Smith, Bioorg. Med. Chem. Lett. 1996, 6, 2387. http://www.sciencedirect.com/science/article/pii/0960894X96004428 </ref>]]
Its selectivity was gained by binding its nitrogens on the benzamidine <scene name='Sean_Swale/Human_Thrombin_Inhibitor/P1_residue/1'>group</scene> by hydrogen bonding to Asp 189, and by fitting its benzamidine benzene into a hydrophobic pocket with Ser 214-Glu 217 and Asp 189-Glu 192 on the other side. The <scene name='Sean_Swale/Human_Thrombin_Inhibitor/P2_proline/1'>proline</scene> residue is in another hydrophobic pocket made up of His 57, Tyr 60A, Leu 99, and Trp 60D. The rest of this structure is unimportant on review of inhibitor 65 because only the amidinobenzylamine which occupies R1 and the proline which occupies the R2 sit are the same residues on inhibitor 65.<ref> M. R. Wiley, N. Y. Chirgadze, D. K. Clawson, T. J. Craft, D. S. GiffordMoore, N. D. Jones, J. L. Olkowski, L. C. Weir, G. F. Smith, Bioorg. Med. Chem. Lett. 1996, 6, 2387. http://www.sciencedirect.com/science/article/pii/0960894X96004428 </ref>

----

===P3 and P4 of Inhibitor 65===
[[Image:Inhibitor 65.png|center|400px|frame|<ref> DOI: 10.1002/cmdc.201200292</ref> ]]
Inhibitor 65 additionally has a <scene name='Sean_Swale/Human_Thrombin_Inhibitor/P4/1'>P4</scene> sulfonyl group with a methoxy group at the end of the residue. The residue sits in a hydrophobic <scene name='Sean_Swale/Human_Thrombin_Inhibitor/P4_binding_pocket/1'>pocket</scene>. It sits in tight VanderWaals structure with the surrounding residues Leu 99, Tyr 60A, Arg 97, Glu 97, and Asn 98.The <scene name='Sean_Swale/Human_Thrombin_Inhibitor/P4_sulfonyl/1'>sulfonyl</scene> group holds its own VanderWaal forces. Additionally, the <scene name='Sean_Swale/Human_Thrombin_Inhibitor/P4_chlorine/1'>chlorine</scene> points to the carbonyl oxygen of Asn 98 and there is a weak Cl-π bond with Trp 215. For the P3 <scene name='Sean_Swale/Human_Thrombin_Inhibitor/P3_binding_site/6'>residue</scene>, there the backbone of asparagine forms and anti parallel beta sheet with Gly 216. The alkylated asparagine’s NH binds to a water molecule which then connects to Glu 192, and the hydrogens of Gly 219 and Gly 216.
[[Image:Thrombin1.gif|left|frame|300px|a) Stereo view of the complete inhibitor structure provided with its electron density in the active site of thrombin. Thrombin is shown with its solvent- accessible surface. b) The P4 sulfonyl residue is located in the aryl binding pocket. The chlorine atom points to the carbonyl oxygen of Asn 98 and accommodates a position above the indole moiety of Trp 215. The methoxy group perfectly fills the upper niche of the S3/4 pocket. c) The P3 side chain is directed into the solvent, where its amide NH binds via a bridging water molecule to Glu 192, Gly 216 and Gly 219.<ref> DOI: 10.1002/cmdc.201200292</ref> ]]

</StructureSection>
This is the <scene name='Sean_Swale/Human_Thrombin_Inhibitor/Thrombin_active_site/2'>active site</scene> of thrombin

[[Image:1ppb-transparent.gif|right|500px|frame|Thrombin with serine residue visible.<ref>January 2002 Molecule of the Month by David Goodsell http://www.rcsb.org/pdb/101/motm.do?momID=25 </ref>]]

==References==
{{reflist}}

Sean Swale/Human Thrombin Inhibitor

2012-11-15T23:54:27Z

Sean Swale:

<StructureSection load='3utu' size='500' frame='false' align='right' |caption='Human Thrombin' scene=''>

===Reasons to develop another <scene name='Sean_Swale/Human_Thrombin_Inhibitor/Active_site/3'>Thrombin</scene> Inhibitor===
Thrombin is a serine protease that cleaves fibrinogen to allow fibrin to form stringy networks that trap red blood cells to form clots. Thrombin is a serine protease because it cleaves fibrinogen with its serine residue. Thrombin when made by the body is tethered to blood vessels so that it cannot cause clots throughout the body causing strokes and heart attacks. Additionally, thrombin is only activated for a few seconds to limit the clotted area to the injured area<ref>January 2002 Molecule of the Month by David Goodsell http://www.rcsb.org/pdb/101/motm.do?momID=25 </ref>. However, when fibrin has accumulated at an injury site, sometimes it will break away and occlude a blood vessel which can cause stroke or heart attack. In order to prevent venous thrombosis, blood clots, after surgery or during dialysis when blood is in contact with artificial devices, Heparin is normally administered. Unfortunately Heparin is neutralized by plasma proteins in the blood, is less efficient for the inhibition of clot bound thrombin, and can trigger an enormous immune response. Antithrombotic drugs like Hirudin will be given if Heparin is not able to be tolerated or if the person receives regular dialysis. Hirudin administration require large doses to maintain proper inhibition of Thrombin which heavily taxes the body. Chemists have been working on designer drugs to increase selectivity and potency. One compound which has shown great selectivity and potency in vitro is <scene name='Sean_Swale/Human_Thrombin_Inhibitor/Inhibitor_65/1'>inhibitor 65</scene>.<ref> DOI: 10.1002/cmdc.201200292</ref>

----

===Phe-Pro-p-amidinobenzylamine===
An early experiment to find a better thrombin inhibitor yielded a structure that was able to bond to the P1 and P2 sites of Thrombin effectively. In 1996 Lilly research laboratories created D-Phe-Pro-p-amidinobenzylamine by making improvements on the previous structure D-Phe-Pro-Agmatine. The new compound they created bonded to thrombin 130x more than it did to trypsin (also a serine protease), and it was highly selective of thrombin over fibrinolytic enzymes which break down fibrin clots. The inhibitor bound with Thrombin at rates 26,000x greater than with plasmin,<ref> http://voices.yahoo.com/what-fibrinolytic-enzymes-6186058.html?cat=68</ref>, 170,000x greater than with t-Pa, and 400,000x greater than with urokinase.
[[Image:1996 inhibitor rates.png|center|600px|frame|Inhibitor 12 is the identical P1 and P2 sites of Inhibitor 65.(1996)<ref> M. R. Wiley, N. Y. Chirgadze, D. K. Clawson, T. J. Craft, D. S. GiffordMoore, N. D. Jones, J. L. Olkowski, L. C. Weir, G. F. Smith, Bioorg. Med. Chem. Lett. 1996, 6, 2387. http://www.sciencedirect.com/science/article/pii/0960894X96004428 </ref>]]
Its selectivity was gained by binding its nitrogens on the benzamidine <scene name='Sean_Swale/Human_Thrombin_Inhibitor/P1_residue/1'>group</scene> by hydrogen bonding to Asp 189, and by fitting its benzamidine benzene into a hydrophobic pocket with Ser 214-Glu 217 and Asp 189-Glu 192 on the other side. The <scene name='Sean_Swale/Human_Thrombin_Inhibitor/P2_proline/1'>proline</scene> residue is in another hydrophobic pocket made up of His 57, Tyr 60A, Leu 99, and Trp 60D. The rest of this structure is unimportant on review of inhibitor 65 because only the amidinobenzylamine which occupies R1 and the proline which occupies the R2 sit are the same residues on inhibitor 65.<ref> M. R. Wiley, N. Y. Chirgadze, D. K. Clawson, T. J. Craft, D. S. GiffordMoore, N. D. Jones, J. L. Olkowski, L. C. Weir, G. F. Smith, Bioorg. Med. Chem. Lett. 1996, 6, 2387. http://www.sciencedirect.com/science/article/pii/0960894X96004428 </ref>

----

===P3 and P4 of Inhibitor 65===
[[Image:Inhibitor 65.png|center|400px|frame|<ref> DOI: 10.1002/cmdc.201200292</ref> ]]
Inhibitor 65 additionally has a <scene name='Sean_Swale/Human_Thrombin_Inhibitor/P4/1'>P4</scene> sulfonyl group with a methoxy group at the end of the residue. The residue sits in a hydrophobic <scene name='Sean_Swale/Human_Thrombin_Inhibitor/P4_binding_pocket/1'>pocket</scene>. It sits in tight VanderWaals structure with the surrounding residues Leu 99, Tyr 60A, Arg 97, Glu 97, and Asn 98.The <scene name='Sean_Swale/Human_Thrombin_Inhibitor/P4_sulfonyl/1'>sulfonyl</scene> group holds its own VanderWaal forces. Additionally, the <scene name='Sean_Swale/Human_Thrombin_Inhibitor/P4_chlorine/1'>chlorine</scene> points to the carbonyl oxygen of Asn 98 and there is a weak Cl-π bond with Trp 215. For the <scene name='Sean_Swale/Human_Thrombin_Inhibitor/P3_binding_site/6'>residue</scene>, there the backbone of asparagine forms and anti parallel beta sheet with Gly 216. The alkylated asparagine’s NH binds to a water molecule which then connects to Glu 192, and the hydrogens of Gly 219 and Gly 216.
[[Image:Thrombin1.gif|left|frame|300px|a) Stereo view of the complete inhibitor structure provided with its electron density in the active site of thrombin. Thrombin is shown with its solvent- accessible surface. b) The P4 sulfonyl residue is located in the aryl binding pocket. The chlorine atom points to the carbonyl oxygen of Asn 98 and accommodates a position above the indole moiety of Trp 215. The methoxy group perfectly fills the upper niche of the S3/4 pocket. c) The P3 side chain is directed into the solvent, where its amide NH binds via a bridging water molecule to Glu 192, Gly 216 and Gly 219.<ref> DOI: 10.1002/cmdc.201200292</ref> ]]

</StructureSection>
This is the <scene name='Sean_Swale/Human_Thrombin_Inhibitor/Thrombin_active_site/2'>active site</scene> of thrombin

[[Image:1ppb-transparent.gif|right|500px|frame|Thrombin with serine residue visible.<ref>January 2002 Molecule of the Month by David Goodsell http://www.rcsb.org/pdb/101/motm.do?momID=25 </ref>]]

==References==
{{reflist}}

Sean Swale/Human Thrombin Inhibitor

2012-11-15T23:49:11Z

Sean Swale:

<StructureSection load='3utu' size='500' frame='false' align='right' |caption='Human Thrombin' scene=''>

===Reasons to develop another <scene name='Sean_Swale/Human_Thrombin_Inhibitor/Active_site/3'>Thrombin</scene> Inhibitor===
Thrombin is a serine protease that cleaves fibrinogen to allow fibrin to form stringy networks that trap red blood cells to form clots. Thrombin is a serine protease because it cleaves fibrinogen with its serine residue. Thrombin when made by the body is tethered to blood vessels so that it cannot cause clots throughout the body causing strokes and heart attacks. Additionally, thrombin is only activated for a few seconds to limit the clotted area to the injured area<ref>January 2002 Molecule of the Month by David Goodsell http://www.rcsb.org/pdb/101/motm.do?momID=25 </ref>. However, when fibrin has accumulated at an injury site, sometimes it will break away and occlude a blood vessel which can cause stroke or heart attack. In order to prevent venous thrombosis, blood clots, after surgery or during dialysis when blood is in contact with artificial devices, Heparin is normally administered. Unfortunately Heparin is neutralized by plasma proteins in the blood, is less efficient for the inhibition of clot bound thrombin, and can trigger an enormous immune response. Antithrombotic drugs like Hirudin will be given if Heparin is not able to be tolerated or if the person receives regular dialysis. Hirudin administration require large doses to maintain proper inhibition of Thrombin which heavily taxes the body. Chemists have been working on designer drugs to increase selectivity and potency. One compound which has shown great selectivity and potency in vitro is <scene name='Sean_Swale/Human_Thrombin_Inhibitor/Inhibitor_65/1'>inhibitor 65</scene>.<ref> DOI: 10.1002/cmdc.201200292</ref>

----

===Phe-Pro-p-amidinobenzylamine===
An early experiment to find a better thrombin inhibitor yielded a structure that was able to bond to the P1 and P2 sites of Thrombin effectively. In 1996 Lilly research laboratories created D-Phe-Pro-p-amidinobenzylamine by making improvements on the previous structure D-Phe-Pro-Agmatine. The new compound they created bonded to thrombin 130x more than it did to trypsin (also a serine protease), and it was highly selective of thrombin over fibrinolytic enzymes which break down fibrin clots. The inhibitor bound with Thrombin at rates 26,000x greater than with plasmin,<ref> http://voices.yahoo.com/what-fibrinolytic-enzymes-6186058.html?cat=68</ref>, 170,000x greater than with t-Pa, and 400,000x greater than with urokinase.
[[Image:1996 inhibitor rates.png|center|600px|frame|Inhibitor 12 is the identical P1 and P2 sites of Inhibitor 65.(1996)<ref> M. R. Wiley, N. Y. Chirgadze, D. K. Clawson, T. J. Craft, D. S. GiffordMoore, N. D. Jones, J. L. Olkowski, L. C. Weir, G. F. Smith, Bioorg. Med. Chem. Lett. 1996, 6, 2387. http://www.sciencedirect.com/science/article/pii/0960894X96004428 </ref>]]
Its selectivity was gained by binding its nitrogens on the benzamidine <scene name='Sean_Swale/Human_Thrombin_Inhibitor/P1_residue/1'>group</scene> by hydrogen bonding to Asp 189, and by fitting its benzamidine benzene into a hydrophobic pocket with Ser 214-Glu 217 and Asp 189-Glu 192 on the other side. The <scene name='Sean_Swale/Human_Thrombin_Inhibitor/P2_proline/1'>proline</scene> residue is in another hydrophobic pocket made up of His 57, Tyr 60A, Leu 99, and Trp 60D. The rest of this structure is unimportant on review of inhibitor 65 because only the amidinobenzylamine which occupies R1 and the proline which occupies the R2 sit are the same residues on inhibitor 65.<ref> M. R. Wiley, N. Y. Chirgadze, D. K. Clawson, T. J. Craft, D. S. GiffordMoore, N. D. Jones, J. L. Olkowski, L. C. Weir, G. F. Smith, Bioorg. Med. Chem. Lett. 1996, 6, 2387. http://www.sciencedirect.com/science/article/pii/0960894X96004428 </ref>

----

===P3 and P4 of Inhibitor 65===
[[Image:Inhibitor 65.png|center|400px|frame|<ref> DOI: 10.1002/cmdc.201200292</ref> ]]
Inhibitor 65 additionally has a <scene name='Sean_Swale/Human_Thrombin_Inhibitor/P4/1'>P4</scene> sulfonyl group with a methoxy group at the end of the residue. The residue sits in a hydrophobic <scene name='Sean_Swale/Human_Thrombin_Inhibitor/P4_binding_pocket/1'>pocket</scene>. It sits in tight VanderWaals structure with the surrounding residues Leu 99, Tyr 60A, Arg 97, Glu 97, and Asn 98.The <scene name='Sean_Swale/Human_Thrombin_Inhibitor/P4_sulfonyl/1'>sulfonyl</scene> group holds its own VanderWaal forces. Additionally, the chlorine points to the carbonyl oxygen of Asn 98 and there is a weak Cl-π bond with Trp 215. For the <scene name='Sean_Swale/Human_Thrombin_Inhibitor/P3_binding_site/6'>residue</scene>, there the backbone of asparagine forms and anti parallel beta sheet with Gly 216. The alkylated asparagine’s NH binds to a water molecule which then connects to Glu 192, and the hydrogens of Gly 219 and Gly 216.
[[Image:Thrombin1.gif|left|frame|300px|a) Stereo view of the complete inhibitor structure provided with its electron density in the active site of thrombin. Thrombin is shown with its solvent- accessible surface. b) The P4 sulfonyl residue is located in the aryl binding pocket. The chlorine atom points to the carbonyl oxygen of Asn 98 and accommodates a position above the indole moiety of Trp 215. The methoxy group perfectly fills the upper niche of the S3/4 pocket. c) The P3 side chain is directed into the solvent, where its amide NH binds via a bridging water molecule to Glu 192, Gly 216 and Gly 219.<ref> DOI: 10.1002/cmdc.201200292</ref> ]]

</StructureSection>
This is the <scene name='Sean_Swale/Human_Thrombin_Inhibitor/Thrombin_active_site/2'>active site</scene> of thrombin

[[Image:1ppb-transparent.gif|right|500px|frame|Thrombin with serine residue visible.<ref>January 2002 Molecule of the Month by David Goodsell http://www.rcsb.org/pdb/101/motm.do?momID=25 </ref>]]

==References==
{{reflist}}

Sean Swale/Human Thrombin Inhibitor

2012-11-15T23:36:25Z

Sean Swale:

<StructureSection load='3utu' size='500' frame='false' align='right' |caption='Human Thrombin' scene=''>

===Reasons to develop another <scene name='Sean_Swale/Human_Thrombin_Inhibitor/Active_site/3'>Thrombin</scene> Inhibitor===
Thrombin is a serine protease that cleaves fibrinogen to allow fibrin to form stringy networks that trap red blood cells to form clots. Thrombin is a serine protease because it cleaves fibrinogen with its serine residue. Thrombin when made by the body is tethered to blood vessels so that it cannot cause clots throughout the body causing strokes and heart attacks. Additionally, thrombin is only activated for a few seconds to limit the clotted area to the injured area<ref>January 2002 Molecule of the Month by David Goodsell http://www.rcsb.org/pdb/101/motm.do?momID=25 </ref>. However, when fibrin has accumulated at an injury site, sometimes it will break away and occlude a blood vessel which can cause stroke or heart attack. In order to prevent venous thrombosis, blood clots, after surgery or during dialysis when blood is in contact with artificial devices, Heparin is normally administered. Unfortunately Heparin is neutralized by plasma proteins in the blood, is less efficient for the inhibition of clot bound thrombin, and can trigger an enormous immune response. Antithrombotic drugs like Hirudin will be given if Heparin is not able to be tolerated or if the person receives regular dialysis. Hirudin administration require large doses to maintain proper inhibition of Thrombin which heavily taxes the body. Chemists have been working on designer drugs to increase selectivity and potency. One compound which has shown great selectivity and potency in vitro is <scene name='Sean_Swale/Human_Thrombin_Inhibitor/Inhibitor_65/1'>inhibitor 65</scene>.<ref> DOI: 10.1002/cmdc.201200292</ref>

----

===Phe-Pro-p-amidinobenzylamine===
An early experiment to find a better thrombin inhibitor yielded a structure that was able to bond to the P1 and P2 sites of Thrombin effectively. In 1996 Lilly research laboratories created D-Phe-Pro-p-amidinobenzylamine by making improvements on the previous structure D-Phe-Pro-Agmatine. The new compound they created bonded to thrombin 130x more than it did to trypsin (also a serine protease), and it was highly selective of thrombin over fibrinolytic enzymes which break down fibrin clots. The inhibitor bound with Thrombin at rates 26,000x greater than with plasmin,<ref> http://voices.yahoo.com/what-fibrinolytic-enzymes-6186058.html?cat=68</ref>, 170,000x greater than with t-Pa, and 400,000x greater than with urokinase.
[[Image:1996 inhibitor rates.png|center|600px|frame|Inhibitor 12 is the identical P1 and P2 sites of Inhibitor 65.(1996)<ref> M. R. Wiley, N. Y. Chirgadze, D. K. Clawson, T. J. Craft, D. S. GiffordMoore, N. D. Jones, J. L. Olkowski, L. C. Weir, G. F. Smith, Bioorg. Med. Chem. Lett. 1996, 6, 2387. http://www.sciencedirect.com/science/article/pii/0960894X96004428 </ref>]]
Its selectivity was gained by binding its nitrogens on the benzamidine <scene name='Sean_Swale/Human_Thrombin_Inhibitor/P1_residue/1'>group</scene> by hydrogen bonding to Asp 189, and by fitting its benzamidine benzene into a hydrophobic pocket with Ser 214-Glu 217 and Asp 189-Glu 192 on the other side. The <scene name='Sean_Swale/Human_Thrombin_Inhibitor/P2_proline/1'>proline</scene> residue is in another hydrophobic pocket made up of His 57, Tyr 60A, Leu 99, and Trp 60D. The rest of this structure is unimportant on review of inhibitor 65 because only the amidinobenzylamine which occupies R1 and the proline which occupies the R2 sit are the same residues on inhibitor 65.<ref> M. R. Wiley, N. Y. Chirgadze, D. K. Clawson, T. J. Craft, D. S. GiffordMoore, N. D. Jones, J. L. Olkowski, L. C. Weir, G. F. Smith, Bioorg. Med. Chem. Lett. 1996, 6, 2387. http://www.sciencedirect.com/science/article/pii/0960894X96004428 </ref>

----

===P3 and P4 of Inhibitor 65===
[[Image:Inhibitor 65.png|center|400px|frame|<ref> DOI: 10.1002/cmdc.201200292</ref> ]]
Inhibitor 65 additionally has a <scene name='Sean_Swale/Human_Thrombin_Inhibitor/P4/1'>P4</scene> sulfonyl group with a methoxy group at the end of the residue. It sits in tight VanderWaals structure with the surrounding residues Leu 99, Tyr 60A, Arg 97, Glu 97, and Asn 98.Additionally, the chlorine points to the carbonyl oxygen of Asn 98 and there is a weak Cl-π bond with Trp 215. For the <scene name='Sean_Swale/Human_Thrombin_Inhibitor/P3_binding_site/6'>residue</scene>, there the backbone of asparagine forms and anti parallel beta sheet with Gly 216. The alkylated asparagine’s NH binds to water which then connects to Glu 192, and the NH of Gly 219 and Gly 216.
[[Image:Thrombin1.gif|left|frame|300px|a) Stereo view of the complete inhibitor structure provided with its electron density in the active site of thrombin. Thrombin is shown with its solvent- accessible surface. b) The P4 sulfonyl residue is located in the aryl binding pocket. The chlorine atom points to the carbonyl oxygen of Asn 98 and accommodates a position above the indole moiety of Trp 215. The methoxy group perfectly fills the upper niche of the S3/4 pocket. c) The P3 side chain is directed into the solvent, where its amide NH binds via a bridging water molecule to Glu 192, Gly 216 and Gly 219.<ref> DOI: 10.1002/cmdc.201200292</ref> ]]

</StructureSection>
This is the <scene name='Sean_Swale/Human_Thrombin_Inhibitor/Thrombin_active_site/2'>active site</scene> of thrombin

[[Image:1ppb-transparent.gif|right|500px|frame|Thrombin with serine residue visible.<ref>January 2002 Molecule of the Month by David Goodsell http://www.rcsb.org/pdb/101/motm.do?momID=25 </ref>]]

==References==
{{reflist}}

Sean Swale/Human Thrombin Inhibitor

2012-11-15T23:25:09Z

Sean Swale:

<StructureSection load='3utu' size='500' frame='false' align='right' |caption='Human Thrombin' scene=''>

===Reasons to develop another <scene name='Sean_Swale/Human_Thrombin_Inhibitor/Active_site/3'>Thrombin</scene> Inhibitor===
Thrombin is a serine protease that cleaves fibrinogen to allow fibrin to form stringy networks that trap red blood cells to form clots. Thrombin is a serine protease because it cleaves fibrinogen with its serine residue. Thrombin when made by the body is tethered to blood vessels so that it cannot cause clots throughout the body causing strokes and heart attacks. Additionally, thrombin is only activated for a few seconds to limit the clotted area to the injured area<ref>January 2002 Molecule of the Month by David Goodsell http://www.rcsb.org/pdb/101/motm.do?momID=25 </ref>. However, when fibrin has accumulated at an injury site, sometimes it will break away and occlude a blood vessel which can cause stroke or heart attack. In order to prevent venous thrombosis, blood clots, after surgery or during dialysis when blood is in contact with artificial devices, Heparin is normally administered. Unfortunately Heparin is neutralized by plasma proteins in the blood, is less efficient for the inhibition of clot bound thrombin, and can trigger an enormous immune response. Antithrombotic drugs like Hirudin will be given if Heparin is not able to be tolerated or if the person receives regular dialysis. Hirudin administration require large doses to maintain proper inhibition of Thrombin which heavily taxes the body. Chemists have been working on designer drugs to increase selectivity and potency. One compound which has shown great selectivity and potency in vitro is <scene name='Sean_Swale/Human_Thrombin_Inhibitor/Inhibitor_65/1'>inhibitor 65</scene>.<ref> DOI: 10.1002/cmdc.201200292</ref>

----

===Phe-Pro-p-amidinobenzylamine===
An early experiment to find a better thrombin inhibitor yielded a structure that was able to bond to the P1 and P2 sites of Thrombin effectively. In 1996 Lilly research laboratories created D-Phe-Pro-p-amidinobenzylamine by making improvements on the previous structure D-Phe-Pro-Agmatine. The new compound they created bonded to thrombin 130x more than it did to trypsin (also a serine protease), and it was highly selective of thrombin over fibrinolytic enzymes which break down fibrin clots. The inhibitor bound with Thrombin at rates 26,000x greater than with plasmin,<ref> http://voices.yahoo.com/what-fibrinolytic-enzymes-6186058.html?cat=68</ref>, 170,000x greater than with t-Pa, and 400,000x greater than with urokinase.
[[Image:1996 inhibitor rates.png|center|600px|frame|Inhibitor 12 is the identical P1 and P2 sites of Inhibitor 65.(1996)<ref> M. R. Wiley, N. Y. Chirgadze, D. K. Clawson, T. J. Craft, D. S. GiffordMoore, N. D. Jones, J. L. Olkowski, L. C. Weir, G. F. Smith, Bioorg. Med. Chem. Lett. 1996, 6, 2387. http://www.sciencedirect.com/science/article/pii/0960894X96004428 </ref>]]
Its selectivity was gained by binding its nitrogens on the benzamidine <scene name='Sean_Swale/Human_Thrombin_Inhibitor/P1_residue/1'>group</scene> by hydrogen bonding to Asp 189, and by fitting its benzamidine benzene into a hydrophobic pocket with Ser 214-Glu 217 and Asp 189-Glu 192 on the other side. The <scene name='Sean_Swale/Human_Thrombin_Inhibitor/P2_proline/1'>proline</scene> residue is in another hydrophobic pocket made up of His 57, Tyr 60A, Leu 99, and Trp 60D. The rest of this structure is unimportant on review of inhibitor 65 because only the amidinobenzylamine which occupies R1 and the proline which occupies the R2 sit are the same residues on inhibitor 65.<ref> M. R. Wiley, N. Y. Chirgadze, D. K. Clawson, T. J. Craft, D. S. GiffordMoore, N. D. Jones, J. L. Olkowski, L. C. Weir, G. F. Smith, Bioorg. Med. Chem. Lett. 1996, 6, 2387. http://www.sciencedirect.com/science/article/pii/0960894X96004428 </ref>

----

===P3 and P4 of Inhibitor 65===
[[Image:Inhibitor 65.png|center|400px|frame|<ref> DOI: 10.1002/cmdc.201200292</ref> ]]
Inhibitor 65 additionally has a P4 sulfonyl group with a methoxy group at the end of the residue. It sits in tight VanderWaals structure with the surrounding residues Leu 99, Tyr 60A, Arg 97, Glu 97, and Asn 98.Additionally, the chlorine points to the carbonyl oxygen of Asn 98 and there is a weak Cl-π bond with Trp 215. For the <scene name='Sean_Swale/Human_Thrombin_Inhibitor/P3_binding_site/6'>residue</scene>, there the backbone of asparagine forms and anti parallel beta sheet with Gly 216. The alkylated asparagine’s NH binds to water which then connects to Glu 192, and the NH of Gly 219 and Gly 216.
[[Image:Thrombin1.gif|left|frame|300px|a) Stereo view of the complete inhibitor structure provided with its electron density in the active site of thrombin. Thrombin is shown with its solvent- accessible surface. b) The P4 sulfonyl residue is located in the aryl binding pocket. The chlorine atom points to the carbonyl oxygen of Asn 98 and accommodates a position above the indole moiety of Trp 215. The methoxy group perfectly fills the upper niche of the S3/4 pocket. c) The P3 side chain is directed into the solvent, where its amide NH binds via a bridging water molecule to Glu 192, Gly 216 and Gly 219.<ref> DOI: 10.1002/cmdc.201200292</ref> ]]

</StructureSection>
This is the <scene name='Sean_Swale/Human_Thrombin_Inhibitor/Thrombin_active_site/2'>active site</scene> of thrombin

[[Image:1ppb-transparent.gif|right|500px|frame|Thrombin with serine residue visible.<ref>January 2002 Molecule of the Month by David Goodsell http://www.rcsb.org/pdb/101/motm.do?momID=25 </ref>]]

==References==
{{reflist}}

Sean Swale/Human Thrombin Inhibitor

2012-11-15T23:21:37Z

Sean Swale:

<StructureSection load='3utu' size='500' frame='false' align='right' |caption='Human Thrombin' scene=''>

===Reasons to develop another <scene name='Sean_Swale/Human_Thrombin_Inhibitor/Active_site/3'>Thrombin</scene> Inhibitor===
Thrombin is a serine protease that cleaves fibrinogen to allow fibrin to form stringy networks that trap red blood cells to form clots. Thrombin is a serine protease because it cleaves fibrinogen with its serine residue. Thrombin when made by the body is tethered to blood vessels so that it cannot cause clots throughout the body causing strokes and heart attacks. Additionally, thrombin is only activated for a few seconds to limit the clotted area to the injured area<ref>January 2002 Molecule of the Month by David Goodsell http://www.rcsb.org/pdb/101/motm.do?momID=25 </ref>. However, when fibrin has accumulated at an injury site, sometimes it will break away and occlude a blood vessel which can cause stroke or heart attack. In order to prevent venous thrombosis, blood clots, after surgery or during dialysis when blood is in contact with artificial devices, Heparin is normally administered. Unfortunately Heparin is neutralized by plasma proteins in the blood, is less efficient for the inhibition of clot bound thrombin, and can trigger an enormous immune response. Antithrombotic drugs like Hirudin will be given if Heparin is not able to be tolerated or if the person receives regular dialysis. Hirudin administration require large doses to maintain proper inhibition of Thrombin which heavily taxes the body. Chemists have been working on designer drugs to increase selectivity and potency. One compound which has shown great selectivity and potency in vitro is <scene name='Sean_Swale/Human_Thrombin_Inhibitor/Inhibitor_65/1'>inhibitor 65</scene>.<ref> DOI: 10.1002/cmdc.201200292</ref>

----

===Phe-Pro-p-amidinobenzylamine===
An early experiment to find a better thrombin inhibitor yielded a structure that was able to bond to the P1 and P2 sites of Thrombin effectively. In 1996 Lilly research laboratories created D-Phe-Pro-p-amidinobenzylamine by making improvements on the previous structure D-Phe-Pro-Agmatine. The new compound they created bonded to thrombin 130x more than it did to trypsin (also a serine protease), and it was highly selective of thrombin over fibrinolytic enzymes which break down fibrin clots. The inhibitor bound with Thrombin at rates 26,000x greater than with plasmin,<ref> http://voices.yahoo.com/what-fibrinolytic-enzymes-6186058.html?cat=68</ref>, 170,000x greater than with t-Pa, and 400,000x greater than with urokinase.
[[Image:1996 inhibitor rates.png|center|600px|frame|Inhibitor 12 is the identical P1 and P2 sites of Inhibitor 65.(1996)<ref> M. R. Wiley, N. Y. Chirgadze, D. K. Clawson, T. J. Craft, D. S. GiffordMoore, N. D. Jones, J. L. Olkowski, L. C. Weir, G. F. Smith, Bioorg. Med. Chem. Lett. 1996, 6, 2387. http://www.sciencedirect.com/science/article/pii/0960894X96004428 </ref>]]
Its selectivity was gained by binding its nitrogens on the benzamidine <scene name='Sean_Swale/Human_Thrombin_Inhibitor/P1_residue/1'>group</scene> by hydrogen bonding to Asp 189, and by fitting its benzamidine benzene into a hydrophobic pocket with Ser 214-Glu 217 and Asp 189-Glu 192 on the other side. The <scene name='Sean_Swale/Human_Thrombin_Inhibitor/P2_proline/1'>proline</scene> residue is in another hydrophobic pocket made up of His 57, Tyr 60A, Leu 99, and Trp 60D. The rest of this structure is unimportant on review of inhibitor 65 because only the amidinobenzylamine which occupies R1 and the proline which occupies the R2 sit are the same residues on inhibitor 65.<ref> M. R. Wiley, N. Y. Chirgadze, D. K. Clawson, T. J. Craft, D. S. GiffordMoore, N. D. Jones, J. L. Olkowski, L. C. Weir, G. F. Smith, Bioorg. Med. Chem. Lett. 1996, 6, 2387. http://www.sciencedirect.com/science/article/pii/0960894X96004428 </ref>

----

===P3 and P4 of Inhibitor 65===
[[Image:Inhibitor 65.png|center|400px|frame|<ref> DOI: 10.1002/cmdc.201200292</ref> ]]
Inhibitor 65 additionally has a P4 sulfonyl group with a methoxy group at the end of the residue. It sits in tight VanderWaals structure with the surrounding residues Leu 99, Tyr 60A, Arg 97, Glu 97, and Asn 98.Additionally, the chlorine points to the carbonyl oxygen of Asn 98 and there is a weak Cl-π bond with Trp 215. For the <scene name='Sean_Swale/Human_Thrombin_Inhibitor/P3_binding_site/5'>residue</scene>, there the backbone of asparagine forms and anti parallel beta sheet with Gly 216. The alkylated asparagine’s NH binds to water which then connects to Glu 192, and the NH of Gly 219 and Gly 216.
[[Image:Thrombin1.gif|left|frame|300px|a) Stereo view of the complete inhibitor structure provided with its electron density in the active site of thrombin. Thrombin is shown with its solvent- accessible surface. b) The P4 sulfonyl residue is located in the aryl binding pocket. The chlorine atom points to the carbonyl oxygen of Asn 98 and accommodates a position above the indole moiety of Trp 215. The methoxy group perfectly fills the upper niche of the S3/4 pocket. c) The P3 side chain is directed into the solvent, where its amide NH binds via a bridging water molecule to Glu 192, Gly 216 and Gly 219.<ref> DOI: 10.1002/cmdc.201200292</ref> ]]

</StructureSection>
This is the <scene name='Sean_Swale/Human_Thrombin_Inhibitor/Thrombin_active_site/2'>active site</scene> of thrombin

[[Image:1ppb-transparent.gif|right|500px|frame|Thrombin with serine residue visible.<ref>January 2002 Molecule of the Month by David Goodsell http://www.rcsb.org/pdb/101/motm.do?momID=25 </ref>]]

==References==
{{reflist}}

Sean Swale/Human Thrombin Inhibitor

2012-11-15T23:16:25Z

Sean Swale:

<StructureSection load='3utu' size='500' frame='false' align='right' |caption='Human Thrombin' scene=''>

===Reasons to develop another <scene name='Sean_Swale/Human_Thrombin_Inhibitor/Active_site/3'>Thrombin</scene> Inhibitor===
Thrombin is a serine protease that cleaves fibrinogen to allow fibrin to form stringy networks that trap red blood cells to form clots. Thrombin is a serine protease because it cleaves fibrinogen with its serine residue. Thrombin when made by the body is tethered to blood vessels so that it cannot cause clots throughout the body causing strokes and heart attacks. Additionally, thrombin is only activated for a few seconds to limit the clotted area to the injured area<ref>January 2002 Molecule of the Month by David Goodsell http://www.rcsb.org/pdb/101/motm.do?momID=25 </ref>. However, when fibrin has accumulated at an injury site, sometimes it will break away and occlude a blood vessel which can cause stroke or heart attack. In order to prevent venous thrombosis, blood clots, after surgery or during dialysis when blood is in contact with artificial devices, Heparin is normally administered. Unfortunately Heparin is neutralized by plasma proteins in the blood, is less efficient for the inhibition of clot bound thrombin, and can trigger an enormous immune response. Antithrombotic drugs like Hirudin will be given if Heparin is not able to be tolerated or if the person receives regular dialysis. Hirudin administration require large doses to maintain proper inhibition of Thrombin which heavily taxes the body. Chemists have been working on designer drugs to increase selectivity and potency. One compound which has shown great selectivity and potency in vitro is <scene name='Sean_Swale/Human_Thrombin_Inhibitor/Inhibitor_65/1'>inhibitor 65</scene>.<ref> DOI: 10.1002/cmdc.201200292</ref>

----

===Phe-Pro-p-amidinobenzylamine===
An early experiment to find a better thrombin inhibitor yielded a structure that was able to bond to the P1 and P2 sites of Thrombin effectively. In 1996 Lilly research laboratories created D-Phe-Pro-p-amidinobenzylamine by making improvements on the previous structure D-Phe-Pro-Agmatine. The new compound they created bonded to thrombin 130x more than it did to trypsin (also a serine protease), and it was highly selective of thrombin over fibrinolytic enzymes which break down fibrin clots. The inhibitor bound with Thrombin at rates 26,000x greater than with plasmin,<ref> http://voices.yahoo.com/what-fibrinolytic-enzymes-6186058.html?cat=68</ref>, 170,000x greater than with t-Pa, and 400,000x greater than with urokinase.
[[Image:1996 inhibitor rates.png|center|600px|frame|Inhibitor 12 is the identical P1 and P2 sites of Inhibitor 65.(1996)<ref> M. R. Wiley, N. Y. Chirgadze, D. K. Clawson, T. J. Craft, D. S. GiffordMoore, N. D. Jones, J. L. Olkowski, L. C. Weir, G. F. Smith, Bioorg. Med. Chem. Lett. 1996, 6, 2387. http://www.sciencedirect.com/science/article/pii/0960894X96004428 </ref>]]
Its selectivity was gained by binding its nitrogens on the benzamidine <scene name='Sean_Swale/Human_Thrombin_Inhibitor/P1_residue/1'>group</scene> by hydrogen bonding to Asp 189, and by fitting its benzamidine benzene into a hydrophobic pocket with Ser 214-Glu 217 and Asp 189-Glu 192 on the other side. The <scene name='Sean_Swale/Human_Thrombin_Inhibitor/P2_proline/1'>proline</scene> residue is in another hydrophobic pocket made up of His 57, Tyr 60A, Leu 99, and Trp 60D. The rest of this structure is unimportant on review of inhibitor 65 because only the amidinobenzylamine which occupies R1 and the proline which occupies the R2 sit are the same residues on inhibitor 65.<ref> M. R. Wiley, N. Y. Chirgadze, D. K. Clawson, T. J. Craft, D. S. GiffordMoore, N. D. Jones, J. L. Olkowski, L. C. Weir, G. F. Smith, Bioorg. Med. Chem. Lett. 1996, 6, 2387. http://www.sciencedirect.com/science/article/pii/0960894X96004428 </ref>

----

===P3 and P4 of Inhibitor 65===
[[Image:Inhibitor 65.png|center|400px|frame|<ref> DOI: 10.1002/cmdc.201200292</ref> ]]
Inhibitor 65 additionally has a P4 sulfonyl group with a methoxy group at the end of the residue. It sits in tight VanderWaals structure with the surrounding residues Leu 99, Tyr 60A, Arg 97, Glu 97, and Asn 98.Additionally, the chlorine points to the carbonyl oxygen of Asn 98 and there is a weak Cl-π bond with Trp 215. For the <scene name='Sean_Swale/Human_Thrombin_Inhibitor/P3_binding_site/3'>P3 residue</scene>, there the backbone of asparagine forms and anti parallel beta sheet with Gly 216. The alkylated asparagine’s NH binds to water which then connects to Glu 192, and the NH of Gly 219 and Gly 216.
[[Image:Thrombin1.gif|left|frame|300px|a) Stereo view of the complete inhibitor structure provided with its electron density in the active site of thrombin. Thrombin is shown with its solvent- accessible surface. b) The P4 sulfonyl residue is located in the aryl binding pocket. The chlorine atom points to the carbonyl oxygen of Asn 98 and accommodates a position above the indole moiety of Trp 215. The methoxy group perfectly fills the upper niche of the S3/4 pocket. c) The P3 side chain is directed into the solvent, where its amide NH binds via a bridging water molecule to Glu 192, Gly 216 and Gly 219.<ref> DOI: 10.1002/cmdc.201200292</ref> ]]

</StructureSection>
This is the <scene name='Sean_Swale/Human_Thrombin_Inhibitor/Thrombin_active_site/2'>active site</scene> of thrombin

[[Image:1ppb-transparent.gif|right|500px|frame|Thrombin with serine residue visible.<ref>January 2002 Molecule of the Month by David Goodsell http://www.rcsb.org/pdb/101/motm.do?momID=25 </ref>]]

==References==
{{reflist}}

Sean Swale/Human Thrombin Inhibitor

2012-11-15T23:11:48Z

Sean Swale:

<StructureSection load='3utu' size='500' frame='false' align='right' |caption='Human Thrombin' scene=''>

===Reasons to develop another <scene name='Sean_Swale/Human_Thrombin_Inhibitor/Active_site/3'>Thrombin</scene> Inhibitor===
Thrombin is a serine protease that cleaves fibrinogen to allow fibrin to form stringy networks that trap red blood cells to form clots. Thrombin is a serine protease because it cleaves fibrinogen with its serine residue. Thrombin when made by the body is tethered to blood vessels so that it cannot cause clots throughout the body causing strokes and heart attacks. Additionally, thrombin is only activated for a few seconds to limit the clotted area to the injured area<ref>January 2002 Molecule of the Month by David Goodsell http://www.rcsb.org/pdb/101/motm.do?momID=25 </ref>. However, when fibrin has accumulated at an injury site, sometimes it will break away and occlude a blood vessel which can cause stroke or heart attack. In order to prevent venous thrombosis, blood clots, after surgery or during dialysis when blood is in contact with artificial devices, Heparin is normally administered. Unfortunately Heparin is neutralized by plasma proteins in the blood, is less efficient for the inhibition of clot bound thrombin, and can trigger an enormous immune response. Antithrombotic drugs like Hirudin will be given if Heparin is not able to be tolerated or if the person receives regular dialysis. Hirudin administration require large doses to maintain proper inhibition of Thrombin which heavily taxes the body. Chemists have been working on designer drugs to increase selectivity and potency. One compound which has shown great selectivity and potency in vitro is <scene name='Sean_Swale/Human_Thrombin_Inhibitor/Inhibitor_65/1'>inhibitor 65</scene>.<ref> DOI: 10.1002/cmdc.201200292</ref>

----

===Phe-Pro-p-amidinobenzylamine===
An early experiment to find a better thrombin inhibitor yielded a structure that was able to bond to the P1 and P2 sites of Thrombin effectively. In 1996 Lilly research laboratories created D-Phe-Pro-p-amidinobenzylamine by making improvements on the previous structure D-Phe-Pro-Agmatine. The new compound they created bonded to thrombin 130x more than it did to trypsin (also a serine protease), and it was highly selective of thrombin over fibrinolytic enzymes which break down fibrin clots. The inhibitor bound with Thrombin at rates 26,000x greater than with plasmin,<ref> http://voices.yahoo.com/what-fibrinolytic-enzymes-6186058.html?cat=68</ref>, 170,000x greater than with t-Pa, and 400,000x greater than with urokinase.
[[Image:1996 inhibitor rates.png|center|600px|frame|Inhibitor 12 is the identical P1 and P2 sites of Inhibitor 65.(1996)<ref> M. R. Wiley, N. Y. Chirgadze, D. K. Clawson, T. J. Craft, D. S. GiffordMoore, N. D. Jones, J. L. Olkowski, L. C. Weir, G. F. Smith, Bioorg. Med. Chem. Lett. 1996, 6, 2387. http://www.sciencedirect.com/science/article/pii/0960894X96004428 </ref>]]
Its selectivity was gained by binding its nitrogens on the benzamidine <scene name='Sean_Swale/Human_Thrombin_Inhibitor/P1_residue/1'>group</scene> by hydrogen bonding to Asp 189, and by fitting its benzamidine benzene into a hydrophobic pocket with Ser 214-Glu 217 and Asp 189-Glu 192 on the other side. The <scene name='Sean_Swale/Human_Thrombin_Inhibitor/P2_proline/1'>proline</scene> residue is in another hydrophobic pocket made up of His 57, Tyr 60A, Leu 99, and Trp 60D. The rest of this structure is unimportant on review of inhibitor 65 because only the amidinobenzylamine which occupies R1 and the proline which occupies the R2 sit are the same residues on inhibitor 65.<ref> M. R. Wiley, N. Y. Chirgadze, D. K. Clawson, T. J. Craft, D. S. GiffordMoore, N. D. Jones, J. L. Olkowski, L. C. Weir, G. F. Smith, Bioorg. Med. Chem. Lett. 1996, 6, 2387. http://www.sciencedirect.com/science/article/pii/0960894X96004428 </ref>

----

===P3 and P4 of Inhibitor 65===
[[Image:Inhibitor 65.png|center|400px|frame|<ref> DOI: 10.1002/cmdc.201200292</ref> ]]
Inhibitor 65 additionally has a P4 sulfonyl group with a methoxy group at the end of the residue. It sits in tight VanderWaals structure with the surrounding residues Leu 99, Tyr 60A, Arg 97, Glu 97, and Asn 98.Additionally, the chlorine points to the carbonyl oxygen of Asn 98 and there is a weak Cl-π bond with Trp 215. For the <scene name='Sean_Swale/Human_Thrombin_Inhibitor/P3_binding_site/2'>P3 residue</scene>, there the backbone of asparagine forms and anti parallel beta sheet with Gly 216. The alkylated asparagine’s NH binds to water which then connects to Glu 192, and the NH of Gly 219 and Gly 216.
[[Image:Thrombin1.gif|left|frame|300px|a) Stereo view of the complete inhibitor structure provided with its electron density in the active site of thrombin. Thrombin is shown with its solvent- accessible surface. b) The P4 sulfonyl residue is located in the aryl binding pocket. The chlorine atom points to the carbonyl oxygen of Asn 98 and accommodates a position above the indole moiety of Trp 215. The methoxy group perfectly fills the upper niche of the S3/4 pocket. c) The P3 side chain is directed into the solvent, where its amide NH binds via a bridging water molecule to Glu 192, Gly 216 and Gly 219.<ref> DOI: 10.1002/cmdc.201200292</ref> ]]

</StructureSection>
This is the <scene name='Sean_Swale/Human_Thrombin_Inhibitor/Thrombin_active_site/2'>active site</scene> of thrombin

[[Image:1ppb-transparent.gif|right|500px|frame|Thrombin with serine residue visible.<ref>January 2002 Molecule of the Month by David Goodsell http://www.rcsb.org/pdb/101/motm.do?momID=25 </ref>]]

==References==
{{reflist}}

Sean Swale/Human Thrombin Inhibitor

2012-11-15T23:10:14Z

Sean Swale:

<StructureSection load='3utu' size='500' frame='false' align='right' |caption='Human Thrombin' scene=''>

===Reasons to develop another <scene name='Sean_Swale/Human_Thrombin_Inhibitor/Active_site/3'>Thrombin</scene> Inhibitor===
Thrombin is a serine protease that cleaves fibrinogen to allow fibrin to form stringy networks that trap red blood cells to form clots. Thrombin is a serine protease because it cleaves fibrinogen with its serine residue. Thrombin when made by the body is tethered to blood vessels so that it cannot cause clots throughout the body causing strokes and heart attacks. Additionally, thrombin is only activated for a few seconds to limit the clotted area to the injured area<ref>January 2002 Molecule of the Month by David Goodsell http://www.rcsb.org/pdb/101/motm.do?momID=25 </ref>. However, when fibrin has accumulated at an injury site, sometimes it will break away and occlude a blood vessel which can cause stroke or heart attack. In order to prevent venous thrombosis, blood clots, after surgery or during dialysis when blood is in contact with artificial devices, Heparin is normally administered. Unfortunately Heparin is neutralized by plasma proteins in the blood, is less efficient for the inhibition of clot bound thrombin, and can trigger an enormous immune response. Antithrombotic drugs like Hirudin will be given if Heparin is not able to be tolerated or if the person receives regular dialysis. Hirudin administration require large doses to maintain proper inhibition of Thrombin which heavily taxes the body. Chemists have been working on designer drugs to increase selectivity and potency. One compound which has shown great selectivity and potency in vitro is <scene name='Sean_Swale/Human_Thrombin_Inhibitor/Inhibitor_65/1'>inhibitor 65</scene>.<ref> DOI: 10.1002/cmdc.201200292</ref>

----

===Phe-Pro-p-amidinobenzylamine===
An early experiment to find a better thrombin inhibitor yielded a structure that was able to bond to the P1 and P2 sites of Thrombin effectively. In 1996 Lilly research laboratories created D-Phe-Pro-p-amidinobenzylamine by making improvements on the previous structure D-Phe-Pro-Agmatine. The new compound they created bonded to thrombin 130x more than it did to trypsin (also a serine protease), and it was highly selective of thrombin over fibrinolytic enzymes which break down fibrin clots. The inhibitor bound with Thrombin at rates 26,000x greater than with plasmin,<ref> http://voices.yahoo.com/what-fibrinolytic-enzymes-6186058.html?cat=68</ref>, 170,000x greater than with t-Pa, and 400,000x greater than with urokinase.
[[Image:1996 inhibitor rates.png|center|600px|frame|Inhibitor 12 is the identical P1 and P2 sites of Inhibitor 65.(1996)<ref> M. R. Wiley, N. Y. Chirgadze, D. K. Clawson, T. J. Craft, D. S. GiffordMoore, N. D. Jones, J. L. Olkowski, L. C. Weir, G. F. Smith, Bioorg. Med. Chem. Lett. 1996, 6, 2387. http://www.sciencedirect.com/science/article/pii/0960894X96004428 </ref>]]
Its selectivity was gained by binding its nitrogens on the benzamidine <scene name='Sean_Swale/Human_Thrombin_Inhibitor/P1_residue/1'>group</scene> by hydrogen bonding to Asp 189, and by fitting its benzamidine benzene into a hydrophobic pocket with Ser 214-Glu 217 and Asp 189-Glu 192 on the other side. The <scene name='Sean_Swale/Human_Thrombin_Inhibitor/P2_proline/1'>proline</scene> residue is in another hydrophobic pocket made up of His 57, Tyr 60A, Leu 99, and Trp 60D. The rest of this structure is unimportant on review of inhibitor 65 because only the amidinobenzylamine which occupies R1 and the proline which occupies the R2 sit are the same residues on inhibitor 65.<ref> M. R. Wiley, N. Y. Chirgadze, D. K. Clawson, T. J. Craft, D. S. GiffordMoore, N. D. Jones, J. L. Olkowski, L. C. Weir, G. F. Smith, Bioorg. Med. Chem. Lett. 1996, 6, 2387. http://www.sciencedirect.com/science/article/pii/0960894X96004428 </ref>

----

===P3 and P4 of Inhibitor 65===
[[Image:Inhibitor 65.png|center|400px|frame|<ref> DOI: 10.1002/cmdc.201200292</ref> ]]
Inhibitor 65 additionally has a P4 sulfonyl group with a methoxy group at the end of the residue. It sits in tight VanderWaals structure with the surrounding residues Leu 99, Tyr 60A, Arg 97, Glu 97, and Asn 98.Additionally, the chlorine points to the carbonyl oxygen of Asn 98 and there is a weak Cl-π bond with Trp 215. For the <scene name='Sean_Swale/Human_Thrombin_Inhibitor/P3_binding_site/1'>P3 residue</scene>, there the backbone of asparagine forms and anti parallel beta sheet with Gly 216. The alkylated asparagine’s NH binds to water which then connects to Glu 192, and the NH of Gly 219 and Gly 216.
[[Image:Thrombin1.gif|left|frame|300px|a) Stereo view of the complete inhibitor structure provided with its electron density in the active site of thrombin. Thrombin is shown with its solvent- accessible surface. b) The P4 sulfonyl residue is located in the aryl binding pocket. The chlorine atom points to the carbonyl oxygen of Asn 98 and accommodates a position above the indole moiety of Trp 215. The methoxy group perfectly fills the upper niche of the S3/4 pocket. c) The P3 side chain is directed into the solvent, where its amide NH binds via a bridging water molecule to Glu 192, Gly 216 and Gly 219.<ref> DOI: 10.1002/cmdc.201200292</ref> ]]

</StructureSection>
This is the <scene name='Sean_Swale/Human_Thrombin_Inhibitor/Thrombin_active_site/2'>active site</scene> of thrombin

[[Image:1ppb-transparent.gif|right|500px|frame|Thrombin with serine residue visible.<ref>January 2002 Molecule of the Month by David Goodsell http://www.rcsb.org/pdb/101/motm.do?momID=25 </ref>]]

==References==
{{reflist}}

Sean Swale/Human Thrombin Inhibitor

2012-11-15T22:45:33Z

Sean Swale:

<StructureSection load='3utu' size='500' frame='false' align='right' |caption='Human Thrombin' scene=''>

===Reasons to develop another <scene name='Sean_Swale/Human_Thrombin_Inhibitor/Active_site/3'>Thrombin</scene> Inhibitor===
Thrombin is a serine protease that cleaves fibrinogen to allow fibrin to form stringy networks that trap red blood cells to form clots. Thrombin is a serine protease because it cleaves fibrinogen with its serine residue. Thrombin when made by the body is tethered to blood vessels so that it cannot cause clots throughout the body causing strokes and heart attacks. Additionally, thrombin is only activated for a few seconds to limit the clotted area to the injured area<ref>January 2002 Molecule of the Month by David Goodsell http://www.rcsb.org/pdb/101/motm.do?momID=25 </ref>. However, when fibrin has accumulated at an injury site, sometimes it will break away and occlude a blood vessel which can cause stroke or heart attack. In order to prevent venous thrombosis, blood clots, after surgery or during dialysis when blood is in contact with artificial devices, Heparin is normally administered. Unfortunately Heparin is neutralized by plasma proteins in the blood, is less efficient for the inhibition of clot bound thrombin, and can trigger an enormous immune response. Antithrombotic drugs like Hirudin will be given if Heparin is not able to be tolerated or if the person receives regular dialysis. Hirudin administration require large doses to maintain proper inhibition of Thrombin which heavily taxes the body. Chemists have been working on designer drugs to increase selectivity and potency. One compound which has shown great selectivity and potency in vitro is <scene name='Sean_Swale/Human_Thrombin_Inhibitor/Inhibitor_65/1'>inhibitor 65</scene>.<ref> DOI: 10.1002/cmdc.201200292</ref>

----

===Phe-Pro-p-amidinobenzylamine===
An early experiment to find a better thrombin inhibitor yielded a structure that was able to bond to the P1 and P2 sites of Thrombin effectively. In 1996 Lilly research laboratories created D-Phe-Pro-p-amidinobenzylamine by making improvements on the previous structure D-Phe-Pro-Agmatine. The new compound they created bonded to thrombin 130x more than it did to trypsin (also a serine protease), and it was highly selective of thrombin over fibrinolytic enzymes which break down fibrin clots. The inhibitor bound with Thrombin at rates 26,000x greater than with plasmin,<ref> http://voices.yahoo.com/what-fibrinolytic-enzymes-6186058.html?cat=68</ref>, 170,000x greater than with t-Pa, and 400,000x greater than with urokinase.
[[Image:1996 inhibitor rates.png|center|600px|frame|Inhibitor 12 is the identical P1 and P2 sites of Inhibitor 65.(1996)<ref> M. R. Wiley, N. Y. Chirgadze, D. K. Clawson, T. J. Craft, D. S. GiffordMoore, N. D. Jones, J. L. Olkowski, L. C. Weir, G. F. Smith, Bioorg. Med. Chem. Lett. 1996, 6, 2387. http://www.sciencedirect.com/science/article/pii/0960894X96004428 </ref>]]
Its selectivity was gained by binding its nitrogens on the benzamidine <scene name='Sean_Swale/Human_Thrombin_Inhibitor/P1_residue/1'>group</scene> by hydrogen bonding to Asp 189, and by fitting its benzamidine benzene into a hydrophobic pocket with Ser 214-Glu 217 and Asp 189-Glu 192 on the other side. The <scene name='Sean_Swale/Human_Thrombin_Inhibitor/P2_proline/1'>proline</scene> residue is in another hydrophobic pocket made up of His 57, Tyr 60A, Leu 99, and Trp 60D. The rest of this structure is unimportant on review of inhibitor 65 because only the amidinobenzylamine which occupies R1 and the proline which occupies the R2 sit are the same residues on inhibitor 65.<ref> M. R. Wiley, N. Y. Chirgadze, D. K. Clawson, T. J. Craft, D. S. GiffordMoore, N. D. Jones, J. L. Olkowski, L. C. Weir, G. F. Smith, Bioorg. Med. Chem. Lett. 1996, 6, 2387. http://www.sciencedirect.com/science/article/pii/0960894X96004428 </ref>

----

===P3 and P4 of Inhibitor 65===
[[Image:Inhibitor 65.png|center|400px|frame|<ref> DOI: 10.1002/cmdc.201200292</ref> ]]
Inhibitor 65 additionally has a P4 sulfonyl group with a methoxy group at the end of the residue. It sits in tight VanderWaals structure with the surrounding residues Leu 99, Tyr 60A, Arg 97, Glu 97, and Asn 98.Additionally, the chlorine points to the carbonyl oxygen of Asn 98 and there is a weak Cl-π bond with Trp 215. For the P3 residue, there the backbone of asparagine forms and anti parallel beta sheet with Gly 216. The alkylated asparagine’s NH binds to water which then connects to Glu 192, and the NH of Gly 219 and Gly 216.
[[Image:Thrombin1.gif|left|frame|300px|a) Stereo view of the complete inhibitor structure provided with its electron density in the active site of thrombin. Thrombin is shown with its solvent- accessible surface. b) The P4 sulfonyl residue is located in the aryl binding pocket. The chlorine atom points to the carbonyl oxygen of Asn 98 and accommodates a position above the indole moiety of Trp 215. The methoxy group perfectly fills the upper niche of the S3/4 pocket. c) The P3 side chain is directed into the solvent, where its amide NH binds via a bridging water molecule to Glu 192, Gly 216 and Gly 219.<ref> DOI: 10.1002/cmdc.201200292</ref> ]]

</StructureSection>
This is the <scene name='Sean_Swale/Human_Thrombin_Inhibitor/Thrombin_active_site/2'>active site</scene> of thrombin

[[Image:1ppb-transparent.gif|right|500px|frame|Thrombin with serine residue visible.<ref>January 2002 Molecule of the Month by David Goodsell http://www.rcsb.org/pdb/101/motm.do?momID=25 </ref>]]

==References==
{{reflist}}

Sean Swale/Human Thrombin Inhibitor

2012-11-15T22:25:33Z

Sean Swale:

<StructureSection load='3utu' size='500' frame='false' align='right' |caption='Human Thrombin' scene=''>

===Reasons to develop another <scene name='Sean_Swale/Human_Thrombin_Inhibitor/Active_site/3'>Thrombin</scene> Inhibitor===
Thrombin is a serine protease that cleaves fibrinogen to allow fibrin to form stringy networks that trap red blood cells to form clots. Thrombin is a serine protease because it cleaves fibrinogen with its serine residue. Thrombin when made by the body is tethered to blood vessels so that it cannot cause clots throughout the body causing strokes and heart attacks. Additionally, thrombin is only activated for a few seconds to limit the clotted area to the injured area<ref>January 2002 Molecule of the Month by David Goodsell http://www.rcsb.org/pdb/101/motm.do?momID=25 </ref>. However, when fibrin has accumulated at an injury site, sometimes it will break away and occlude a blood vessel which can cause stroke or heart attack. In order to prevent venous thrombosis, blood clots, after surgery or during dialysis when blood is in contact with artificial devices, Heparin is normally administered. Unfortunately Heparin is neutralized by plasma proteins in the blood, is less efficient for the inhibition of clot bound thrombin, and can trigger an enormous immune response. Antithrombotic drugs like Hirudin will be given if Heparin is not able to be tolerated or if the person receives regular dialysis. Hirudin administration require large doses to maintain proper inhibition of Thrombin which heavily taxes the body. Chemists have been working on designer drugs to increase selectivity and potency. One compound which has shown great selectivity and potency in vitro is <scene name='Sean_Swale/Human_Thrombin_Inhibitor/Inhibitor_65/1'>inhibitor 65</scene>.<ref> DOI: 10.1002/cmdc.201200292</ref>

----

===Phe-Pro-p-amidinobenzylamine===
An early experiment to find a better thrombin inhibitor yielded a structure that was able to bond to the P1 and P2 sites of Thrombin effectively. In 1996 Lilly research laboratories created D-Phe-Pro-p-amidinobenzylamine by making improvements on the previous structure D-Phe-Pro-Agmatine. The new compound they created bonded to thrombin 130x more than it did to trypsin (also a serine protease), and it was highly selective of thrombin over fibrinolytic enzymes which break down fibrin clots. The inhibitor bound with Thrombin at rates 26,000x greater than with plasmin,<ref> http://voices.yahoo.com/what-fibrinolytic-enzymes-6186058.html?cat=68</ref>, 170,000x greater than with t-Pa, and 400,000x greater than with urokinase.
[[Image:1996 inhibitor rates.png|center|600px|frame|Inhibitor 12 is the identical P1 and P2 sites of Inhibitor 65.(1996)<ref> M. R. Wiley, N. Y. Chirgadze, D. K. Clawson, T. J. Craft, D. S. GiffordMoore, N. D. Jones, J. L. Olkowski, L. C. Weir, G. F. Smith, Bioorg. Med. Chem. Lett. 1996, 6, 2387. http://www.sciencedirect.com/science/article/pii/0960894X96004428 </ref>]]
Its selectivity was gained by binding its nitrogens on the benzamidine <scene name='Sean_Swale/Human_Thrombin_Inhibitor/P1_residue/1'>group</scene> by hydrogen bonding to Asp 189, and by fitting its benzamidine benzene into a hydrophobic pocket with Ser 214-Glu 217 and Asp 189-Glu 192 on the other side. The proline residue is in another hydrophobic pocket made up of His 57, Tyr 60A, Leu 99, and Trp 60D. The rest of this structure is unimportant on review of inhibitor 65 because only the amidinobenzylamine which occupies R1 and the proline which occupies the R2 sit are the same residues on inhibitor 65.<ref> M. R. Wiley, N. Y. Chirgadze, D. K. Clawson, T. J. Craft, D. S. GiffordMoore, N. D. Jones, J. L. Olkowski, L. C. Weir, G. F. Smith, Bioorg. Med. Chem. Lett. 1996, 6, 2387. http://www.sciencedirect.com/science/article/pii/0960894X96004428 </ref>

----

===P3 and P4 of Inhibitor 65===
[[Image:Inhibitor 65.png|center|400px|frame|<ref> DOI: 10.1002/cmdc.201200292</ref> ]]
Inhibitor 65 additionally has a P4 sulfonyl group with a methoxy group at the end of the residue. It sits in tight VanderWaals structure with the surrounding residues Leu 99, Tyr 60A, Arg 97, Glu 97, and Asn 98.Additionally, the chlorine points to the carbonyl oxygen of Asn 98 and there is a weak Cl-π bond with Trp 215. For the P3 residue, there the backbone of asparagine forms and anti parallel beta sheet with Gly 216. The alkylated asparagine’s NH binds to water which then connects to Glu 192, and the NH of Gly 219 and Gly 216.
[[Image:Thrombin1.gif|left|frame|300px|a) Stereo view of the complete inhibitor structure provided with its electron density in the active site of thrombin. Thrombin is shown with its solvent- accessible surface. b) The P4 sulfonyl residue is located in the aryl binding pocket. The chlorine atom points to the carbonyl oxygen of Asn 98 and accommodates a position above the indole moiety of Trp 215. The methoxy group perfectly fills the upper niche of the S3/4 pocket. c) The P3 side chain is directed into the solvent, where its amide NH binds via a bridging water molecule to Glu 192, Gly 216 and Gly 219.<ref> DOI: 10.1002/cmdc.201200292</ref> ]]

</StructureSection>
This is the <scene name='Sean_Swale/Human_Thrombin_Inhibitor/Thrombin_active_site/2'>active site</scene> of thrombin

[[Image:1ppb-transparent.gif|right|500px|frame|Thrombin with serine residue visible.<ref>January 2002 Molecule of the Month by David Goodsell http://www.rcsb.org/pdb/101/motm.do?momID=25 </ref>]]

==References==
{{reflist}}

Sean Swale/Human Thrombin Inhibitor

2012-11-15T22:16:15Z

Sean Swale:

<StructureSection load='3utu' size='500' frame='false' align='right' |caption='Human Thrombin' scene=''>

===Reasons to develop another <scene name='Sean_Swale/Human_Thrombin_Inhibitor/Active_site/3'>Thrombin</scene> Inhibitor===
Thrombin is a serine protease that cleaves fibrinogen to allow fibrin to form stringy networks that trap red blood cells to form clots. Thrombin is a serine protease because it cleaves fibrinogen with its serine residue. Thrombin when made by the body is tethered to blood vessels so that it cannot cause clots throughout the body causing strokes and heart attacks. Additionally, thrombin is only activated for a few seconds to limit the clotted area to the injured area<ref>January 2002 Molecule of the Month by David Goodsell http://www.rcsb.org/pdb/101/motm.do?momID=25 </ref>. However, when fibrin has accumulated at an injury site, sometimes it will break away and occlude a blood vessel which can cause stroke or heart attack. In order to prevent venous thrombosis, blood clots, after surgery or during dialysis when blood is in contact with artificial devices, Heparin is normally administered. Unfortunately Heparin is neutralized by plasma proteins in the blood, is less efficient for the inhibition of clot bound thrombin, and can trigger an enormous immune response. Antithrombotic drugs like Hirudin will be given if Heparin is not able to be tolerated or if the person receives regular dialysis. Hirudin administration require large doses to maintain proper inhibition of Thrombin which heavily taxes the body. Chemists have been working on designer drugs to increase selectivity and potency. One compound which has shown great selectivity and potency in vitro is <scene name='Sean_Swale/Human_Thrombin_Inhibitor/Inhibitor_65/1'>inhibitor 65</scene>.<ref> DOI: 10.1002/cmdc.201200292</ref>

----

===Phe-Pro-p-amidinobenzylamine===
An early experiment to find a better thrombin inhibitor yielded a structure that was able to bond to the P1 and P2 sites of Thrombin effectively. In 1996 Lilly research laboratories created D-Phe-Pro-p-amidinobenzylamine by making improvements on the previous structure D-Phe-Pro-Agmatine. The new compound they created bonded to thrombin 130x more than it did to trypsin (also a serine protease), and it was highly selective of thrombin over fibrinolytic enzymes which break down fibrin clots. The inhibitor bound with Thrombin at rates 26,000x greater than with plasmin,<ref> http://voices.yahoo.com/what-fibrinolytic-enzymes-6186058.html?cat=68</ref>, 170,000x greater than with t-Pa, and 400,000x greater than with urokinase.
[[Image:1996 inhibitor rates.png|center|600px|frame|Inhibitor 12 is the identical P1 and P2 sites of Inhibitor 65.(1996)<ref> M. R. Wiley, N. Y. Chirgadze, D. K. Clawson, T. J. Craft, D. S. GiffordMoore, N. D. Jones, J. L. Olkowski, L. C. Weir, G. F. Smith, Bioorg. Med. Chem. Lett. 1996, 6, 2387. http://www.sciencedirect.com/science/article/pii/0960894X96004428 </ref>]]
Its selectivity was gained by <scene name='Sean_Swale/Human_Thrombin_Inhibitor/P1_site/4'>binding</scene> its nitrogens on the benzamidine group by hydrogen bonding to Asp 189, and by fitting its benzamidine benzene into a hydrophobic pocket with Ser 214-Glu 217 and Asp 189-Glu 192 on the other side. The proline residue is in another hydrophobic pocket made up of His 57, Tyr 60A, Leu 99, and Trp 60D. The rest of this structure is unimportant on review of inhibitor 65 because only the amidinobenzylamine which occupies R1 and the proline which occupies the R2 sit are the same residues on inhibitor 65.<ref> M. R. Wiley, N. Y. Chirgadze, D. K. Clawson, T. J. Craft, D. S. GiffordMoore, N. D. Jones, J. L. Olkowski, L. C. Weir, G. F. Smith, Bioorg. Med. Chem. Lett. 1996, 6, 2387. http://www.sciencedirect.com/science/article/pii/0960894X96004428 </ref>

----

===P3 and P4 of Inhibitor 65===
[[Image:Inhibitor 65.png|center|400px|frame|<ref> DOI: 10.1002/cmdc.201200292</ref> ]]
Inhibitor 65 additionally has a P4 sulfonyl group with a methoxy group at the end of the residue. It sits in tight VanderWaals structure with the surrounding residues Leu 99, Tyr 60A, Arg 97, Glu 97, and Asn 98.Additionally, the chlorine points to the carbonyl oxygen of Asn 98 and there is a weak Cl-π bond with Trp 215. For the P3 residue, there the backbone of asparagine forms and anti parallel beta sheet with Gly 216. The alkylated asparagine’s NH binds to water which then connects to Glu 192, and the NH of Gly 219 and Gly 216.
[[Image:Thrombin1.gif|left|frame|300px|a) Stereo view of the complete inhibitor structure provided with its electron density in the active site of thrombin. Thrombin is shown with its solvent- accessible surface. b) The P4 sulfonyl residue is located in the aryl binding pocket. The chlorine atom points to the carbonyl oxygen of Asn 98 and accommodates a position above the indole moiety of Trp 215. The methoxy group perfectly fills the upper niche of the S3/4 pocket. c) The P3 side chain is directed into the solvent, where its amide NH binds via a bridging water molecule to Glu 192, Gly 216 and Gly 219.<ref> DOI: 10.1002/cmdc.201200292</ref> ]]

</StructureSection>
This is the <scene name='Sean_Swale/Human_Thrombin_Inhibitor/Thrombin_active_site/2'>active site</scene> of thrombin

[[Image:1ppb-transparent.gif|right|500px|frame|Thrombin with serine residue visible.<ref>January 2002 Molecule of the Month by David Goodsell http://www.rcsb.org/pdb/101/motm.do?momID=25 </ref>]]

==References==
{{reflist}}

Sean Swale/Human Thrombin Inhibitor

2012-11-15T22:14:30Z

Sean Swale:

<StructureSection load='3utu' size='500' frame='false' align='right' |caption='Human Thrombin' scene=''>

===Reasons to develop another <scene name='Sean_Swale/Human_Thrombin_Inhibitor/Active_site/3'>Thrombin</scene> Inhibitor===
Thrombin is a serine protease that cleaves fibrinogen to allow fibrin to form stringy networks that trap red blood cells to form clots. Thrombin is a serine protease because it cleaves fibrinogen with its serine residue. Thrombin when made by the body is tethered to blood vessels so that it cannot cause clots throughout the body causing strokes and heart attacks. Additionally, thrombin is only activated for a few seconds to limit the clotted area to the injured area<ref>January 2002 Molecule of the Month by David Goodsell http://www.rcsb.org/pdb/101/motm.do?momID=25 </ref>. However, when fibrin has accumulated at an injury site, sometimes it will break away and occlude a blood vessel which can cause stroke or heart attack. In order to prevent venous thrombosis, blood clots, after surgery or during dialysis when blood is in contact with artificial devices, Heparin is normally administered. Unfortunately Heparin is neutralized by plasma proteins in the blood, is less efficient for the inhibition of clot bound thrombin, and can trigger an enormous immune response. Antithrombotic drugs like Hirudin will be given if Heparin is not able to be tolerated or if the person receives regular dialysis. Hirudin administration require large doses to maintain proper inhibition of Thrombin which heavily taxes the body. Chemists have been working on designer drugs to increase selectivity and potency. One compound which has shown great selectivity and potency in vitro is <scene name='Sean_Swale/Human_Thrombin_Inhibitor/Inhibitor_65/1'>inhibitor 65</scene>.<ref> DOI: 10.1002/cmdc.201200292</ref>

----

===Phe-Pro-p-amidinobenzylamine===
An early experiment to find a better thrombin inhibitor yielded a structure that was able to bond to the P1 and P2 sites of Thrombin effectively. In 1996 Lilly research laboratories created D-Phe-Pro-p-amidinobenzylamine by making improvements on the previous structure D-Phe-Pro-Agmatine. The new compound they created bonded to thrombin 130x more than it did to trypsin (also a serine protease), and it was highly selective of thrombin over fibrinolytic enzymes which break down fibrin clots. The inhibitor bound with Thrombin at rates 26,000x greater than with plasmin,<ref> http://voices.yahoo.com/what-fibrinolytic-enzymes-6186058.html?cat=68</ref>, 170,000x greater than with t-Pa, and 400,000x greater than with urokinase.
[[Image:1996 inhibitor rates.png|center|600px|frame|Inhibitor 12 is the identical P1 and P2 sites of Inhibitor 65.(1996)<ref> M. R. Wiley, N. Y. Chirgadze, D. K. Clawson, T. J. Craft, D. S. GiffordMoore, N. D. Jones, J. L. Olkowski, L. C. Weir, G. F. Smith, Bioorg. Med. Chem. Lett. 1996, 6, 2387. http://www.sciencedirect.com/science/article/pii/0960894X96004428 </ref>]]
Its selectivity was gained by <scene name='Sean_Swale/Human_Thrombin_Inhibitor/P1_site/3'>binding</scene> its nitrogens on the benzamidine group by hydrogen bonding to Asp 189, and by fitting its benzamidine benzene into a hydrophobic pocket with Ser 214-Glu 217 and Asp 189-Glu 192 on the other side. The proline residue is in another hydrophobic pocket made up of His 57, Tyr 60A, Leu 99, and Trp 60D. The rest of this structure is unimportant on review of inhibitor 65 because only the amidinobenzylamine which occupies R1 and the proline which occupies the R2 sit are the same residues on inhibitor 65.<ref> M. R. Wiley, N. Y. Chirgadze, D. K. Clawson, T. J. Craft, D. S. GiffordMoore, N. D. Jones, J. L. Olkowski, L. C. Weir, G. F. Smith, Bioorg. Med. Chem. Lett. 1996, 6, 2387. http://www.sciencedirect.com/science/article/pii/0960894X96004428 </ref>

----

===P3 and P4 of Inhibitor 65===
[[Image:Inhibitor 65.png|center|400px|frame|<ref> DOI: 10.1002/cmdc.201200292</ref> ]]
Inhibitor 65 additionally has a P4 sulfonyl group with a methoxy group at the end of the residue. It sits in tight VanderWaals structure with the surrounding residues Leu 99, Tyr 60A, Arg 97, Glu 97, and Asn 98.Additionally, the chlorine points to the carbonyl oxygen of Asn 98 and there is a weak Cl-π bond with Trp 215. For the P3 residue, there the backbone of asparagine forms and anti parallel beta sheet with Gly 216. The alkylated asparagine’s NH binds to water which then connects to Glu 192, and the NH of Gly 219 and Gly 216.
[[Image:Thrombin1.gif|left|frame|300px|a) Stereo view of the complete inhibitor structure provided with its electron density in the active site of thrombin. Thrombin is shown with its solvent- accessible surface. b) The P4 sulfonyl residue is located in the aryl binding pocket. The chlorine atom points to the carbonyl oxygen of Asn 98 and accommodates a position above the indole moiety of Trp 215. The methoxy group perfectly fills the upper niche of the S3/4 pocket. c) The P3 side chain is directed into the solvent, where its amide NH binds via a bridging water molecule to Glu 192, Gly 216 and Gly 219.<ref> DOI: 10.1002/cmdc.201200292</ref> ]]

</StructureSection>
This is the <scene name='Sean_Swale/Human_Thrombin_Inhibitor/Thrombin_active_site/2'>active site</scene> of thrombin

[[Image:1ppb-transparent.gif|right|500px|frame|Thrombin with serine residue visible.<ref>January 2002 Molecule of the Month by David Goodsell http://www.rcsb.org/pdb/101/motm.do?momID=25 </ref>]]

==References==
{{reflist}}

Sean Swale/Human Thrombin Inhibitor

2012-11-15T22:11:12Z

Sean Swale:

<StructureSection load='3utu' size='500' frame='false' align='right' |caption='Human Thrombin' scene=''>

===Reasons to develop another <scene name='Sean_Swale/Human_Thrombin_Inhibitor/Active_site/3'>Thrombin</scene> Inhibitor===
Thrombin is a serine protease that cleaves fibrinogen to allow fibrin to form stringy networks that trap red blood cells to form clots. Thrombin is a serine protease because it cleaves fibrinogen with its serine residue. Thrombin when made by the body is tethered to blood vessels so that it cannot cause clots throughout the body causing strokes and heart attacks. Additionally, thrombin is only activated for a few seconds to limit the clotted area to the injured area<ref>January 2002 Molecule of the Month by David Goodsell http://www.rcsb.org/pdb/101/motm.do?momID=25 </ref>. However, when fibrin has accumulated at an injury site, sometimes it will break away and occlude a blood vessel which can cause stroke or heart attack. In order to prevent venous thrombosis, blood clots, after surgery or during dialysis when blood is in contact with artificial devices, Heparin is normally administered. Unfortunately Heparin is neutralized by plasma proteins in the blood, is less efficient for the inhibition of clot bound thrombin, and can trigger an enormous immune response. Antithrombotic drugs like Hirudin will be given if Heparin is not able to be tolerated or if the person receives regular dialysis. Hirudin administration require large doses to maintain proper inhibition of Thrombin which heavily taxes the body. Chemists have been working on designer drugs to increase selectivity and potency. One compound which has shown great selectivity and potency in vitro is <scene name='Sean_Swale/Human_Thrombin_Inhibitor/Inhibitor_65/1'>inhibitor 65</scene>.<ref> DOI: 10.1002/cmdc.201200292</ref>

----

===Phe-Pro-p-amidinobenzylamine===
An early experiment to find a better thrombin inhibitor yielded a structure that was able to bond to the P1 and P2 sites of Thrombin effectively. In 1996 Lilly research laboratories created D-Phe-Pro-p-amidinobenzylamine by making improvements on the previous structure D-Phe-Pro-Agmatine. The new compound they created bonded to thrombin 130x more than it did to trypsin (also a serine protease), and it was highly selective of thrombin over fibrinolytic enzymes which break down fibrin clots. The inhibitor bound with Thrombin at rates 26,000x greater than with plasmin,<ref> http://voices.yahoo.com/what-fibrinolytic-enzymes-6186058.html?cat=68</ref>, 170,000x greater than with t-Pa, and 400,000x greater than with urokinase.
[[Image:1996 inhibitor rates.png|center|600px|frame|Inhibitor 12 is the identical P1 and P2 sites of Inhibitor 65.(1996)<ref> M. R. Wiley, N. Y. Chirgadze, D. K. Clawson, T. J. Craft, D. S. GiffordMoore, N. D. Jones, J. L. Olkowski, L. C. Weir, G. F. Smith, Bioorg. Med. Chem. Lett. 1996, 6, 2387. http://www.sciencedirect.com/science/article/pii/0960894X96004428 </ref>]]
Its selectivity was gained by <scene name='Sean_Swale/Human_Thrombin_Inhibitor/P1_site/2'>binding</scene> its nitrogens on the benzamidine group by hydrogen bonding to Asp 189, and by fitting its benzamidine benzene into a hydrophobic pocket with Ser 214-Glu 217 and Asp 189-Glu 192 on the other side. The proline residue is in another hydrophobic pocket made up of His 57, Tyr 60A, Leu 99, and Trp 60D. The rest of this structure is unimportant on review of inhibitor 65 because only the amidinobenzylamine which occupies R1 and the proline which occupies the R2 sit are the same residues on inhibitor 65.<ref> M. R. Wiley, N. Y. Chirgadze, D. K. Clawson, T. J. Craft, D. S. GiffordMoore, N. D. Jones, J. L. Olkowski, L. C. Weir, G. F. Smith, Bioorg. Med. Chem. Lett. 1996, 6, 2387. http://www.sciencedirect.com/science/article/pii/0960894X96004428 </ref>

----

===P3 and P4 of Inhibitor 65===
[[Image:Inhibitor 65.png|center|400px|frame|<ref> DOI: 10.1002/cmdc.201200292</ref> ]]
Inhibitor 65 additionally has a P4 sulfonyl group with a methoxy group at the end of the residue. It sits in tight VanderWaals structure with the surrounding residues Leu 99, Tyr 60A, Arg 97, Glu 97, and Asn 98.Additionally, the chlorine points to the carbonyl oxygen of Asn 98 and there is a weak Cl-π bond with Trp 215. For the P3 residue, there the backbone of asparagine forms and anti parallel beta sheet with Gly 216. The alkylated asparagine’s NH binds to water which then connects to Glu 192, and the NH of Gly 219 and Gly 216.
[[Image:Thrombin1.gif|left|frame|300px|a) Stereo view of the complete inhibitor structure provided with its electron density in the active site of thrombin. Thrombin is shown with its solvent- accessible surface. b) The P4 sulfonyl residue is located in the aryl binding pocket. The chlorine atom points to the carbonyl oxygen of Asn 98 and accommodates a position above the indole moiety of Trp 215. The methoxy group perfectly fills the upper niche of the S3/4 pocket. c) The P3 side chain is directed into the solvent, where its amide NH binds via a bridging water molecule to Glu 192, Gly 216 and Gly 219.<ref> DOI: 10.1002/cmdc.201200292</ref> ]]

</StructureSection>
This is the <scene name='Sean_Swale/Human_Thrombin_Inhibitor/Thrombin_active_site/2'>active site</scene> of thrombin

[[Image:1ppb-transparent.gif|right|500px|frame|Thrombin with serine residue visible.<ref>January 2002 Molecule of the Month by David Goodsell http://www.rcsb.org/pdb/101/motm.do?momID=25 </ref>]]

==References==
{{reflist}}

Sean Swale/Human Thrombin Inhibitor

2012-11-15T22:07:38Z

Sean Swale:

<StructureSection load='3utu' size='500' frame='false' align='right' |caption='Human Thrombin' scene=''>

===Reasons to develop another <scene name='Sean_Swale/Human_Thrombin_Inhibitor/Active_site/3'>Thrombin</scene> Inhibitor===
Thrombin is a serine protease that cleaves fibrinogen to allow fibrin to form stringy networks that trap red blood cells to form clots. Thrombin is a serine protease because it cleaves fibrinogen with its serine residue. Thrombin when made by the body is tethered to blood vessels so that it cannot cause clots throughout the body causing strokes and heart attacks. Additionally, thrombin is only activated for a few seconds to limit the clotted area to the injured area<ref>January 2002 Molecule of the Month by David Goodsell http://www.rcsb.org/pdb/101/motm.do?momID=25 </ref>. However, when fibrin has accumulated at an injury site, sometimes it will break away and occlude a blood vessel which can cause stroke or heart attack. In order to prevent venous thrombosis, blood clots, after surgery or during dialysis when blood is in contact with artificial devices, Heparin is normally administered. Unfortunately Heparin is neutralized by plasma proteins in the blood, is less efficient for the inhibition of clot bound thrombin, and can trigger an enormous immune response. Antithrombotic drugs like Hirudin will be given if Heparin is not able to be tolerated or if the person receives regular dialysis. Hirudin administration require large doses to maintain proper inhibition of Thrombin which heavily taxes the body. Chemists have been working on designer drugs to increase selectivity and potency. One compound which has shown great selectivity and potency in vitro is <scene name='Sean_Swale/Human_Thrombin_Inhibitor/Inhibitor_65/1'>inhibitor 65</scene>.<ref> DOI: 10.1002/cmdc.201200292</ref>

----

===Phe-Pro-p-amidinobenzylamine===
An early experiment to find a better thrombin inhibitor yielded a structure that was able to bond to the P1 and P2 sites of Thrombin effectively. In 1996 Lilly research laboratories created D-Phe-Pro-p-amidinobenzylamine by making improvements on the previous structure D-Phe-Pro-Agmatine. The new compound they created bonded to thrombin 130x more than it did to trypsin (also a serine protease), and it was highly selective of thrombin over fibrinolytic enzymes which break down fibrin clots. The inhibitor bound with Thrombin at rates 26,000x greater than with plasmin,<ref> http://voices.yahoo.com/what-fibrinolytic-enzymes-6186058.html?cat=68</ref>, 170,000x greater than with t-Pa, and 400,000x greater than with urokinase.
[[Image:1996 inhibitor rates.png|center|600px|frame|Inhibitor 12 is the identical P1 and P2 sites of Inhibitor 65.(1996)<ref> M. R. Wiley, N. Y. Chirgadze, D. K. Clawson, T. J. Craft, D. S. GiffordMoore, N. D. Jones, J. L. Olkowski, L. C. Weir, G. F. Smith, Bioorg. Med. Chem. Lett. 1996, 6, 2387. http://www.sciencedirect.com/science/article/pii/0960894X96004428 </ref>]]
Its selectivity was gained by <scene name='Sean_Swale/Human_Thrombin_Inhibitor/P1_site/1'>binding</scene>its nitrogens on the benzamidine group by hydrogen bonding to Asp 189, and by fitting its benzamidine benzene into a hydrophobic pocket with Ser 214-Glu 217 and Asp 189-Glu 192 on the other side. The proline residue is in another hydrophobic pocket made up of His 57, Tyr 60A, Leu 99, and Trp 60D. The rest of this structure is unimportant on review of inhibitor 65 because only the amidinobenzylamine which occupies R1 and the proline which occupies the R2 sit are the same residues on inhibitor 65.<ref> M. R. Wiley, N. Y. Chirgadze, D. K. Clawson, T. J. Craft, D. S. GiffordMoore, N. D. Jones, J. L. Olkowski, L. C. Weir, G. F. Smith, Bioorg. Med. Chem. Lett. 1996, 6, 2387. http://www.sciencedirect.com/science/article/pii/0960894X96004428 </ref>

----

===P3 and P4 of Inhibitor 65===
[[Image:Inhibitor 65.png|center|400px|frame|<ref> DOI: 10.1002/cmdc.201200292</ref> ]]
Inhibitor 65 additionally has a P4 sulfonyl group with a methoxy group at the end of the residue. It sits in tight VanderWaals structure with the surrounding residues Leu 99, Tyr 60A, Arg 97, Glu 97, and Asn 98.Additionally, the chlorine points to the carbonyl oxygen of Asn 98 and there is a weak Cl-π bond with Trp 215. For the P3 residue, there the backbone of asparagine forms and anti parallel beta sheet with Gly 216. The alkylated asparagine’s NH binds to water which then connects to Glu 192, and the NH of Gly 219 and Gly 216.
[[Image:Thrombin1.gif|left|frame|300px|a) Stereo view of the complete inhibitor structure provided with its electron density in the active site of thrombin. Thrombin is shown with its solvent- accessible surface. b) The P4 sulfonyl residue is located in the aryl binding pocket. The chlorine atom points to the carbonyl oxygen of Asn 98 and accommodates a position above the indole moiety of Trp 215. The methoxy group perfectly fills the upper niche of the S3/4 pocket. c) The P3 side chain is directed into the solvent, where its amide NH binds via a bridging water molecule to Glu 192, Gly 216 and Gly 219.<ref> DOI: 10.1002/cmdc.201200292</ref> ]]

</StructureSection>
This is the <scene name='Sean_Swale/Human_Thrombin_Inhibitor/Thrombin_active_site/2'>active site</scene> of thrombin

[[Image:1ppb-transparent.gif|right|500px|frame|Thrombin with serine residue visible.<ref>January 2002 Molecule of the Month by David Goodsell http://www.rcsb.org/pdb/101/motm.do?momID=25 </ref>]]

==References==
{{reflist}}

Sean Swale/Human Thrombin Inhibitor

2012-11-15T21:41:28Z

Sean Swale:

<StructureSection load='3utu' size='500' frame='false' align='right' |caption='Human Thrombin' scene=''>

===Reasons to develop another <scene name='Sean_Swale/Human_Thrombin_Inhibitor/Active_site/1'>Thrombin</scene> Inhibitor===
Thrombin is a serine protease that cleaves fibrinogen to allow fibrin to form stringy networks that trap red blood cells to form clots. Thrombin is a serine protease because it cleaves fibrinogen with its serine residue. Thrombin when made by the body is tethered to blood vessels so that it cannot cause clots throughout the body causing strokes and heart attacks. Additionally, thrombin is only activated for a few seconds to limit the clotted area to the injured area<ref>January 2002 Molecule of the Month by David Goodsell http://www.rcsb.org/pdb/101/motm.do?momID=25 </ref>. However, when fibrin has accumulated at an injury site, sometimes it will break away and occlude a blood vessel which can cause stroke or heart attack. In order to prevent venous thrombosis, blood clots, after surgery or during dialysis when blood is in contact with artificial devices, Heparin is normally administered. Unfortunately Heparin is neutralized by plasma proteins in the blood, is less efficient for the inhibition of clot bound thrombin, and can trigger an enormous immune response. Antithrombotic drugs like Hirudin will be given if Heparin is not able to be tolerated or if the person receives regular dialysis. Hirudin administration require large doses to maintain proper inhibition of Thrombin which heavily taxes the body. Chemists have been working on designer drugs to increase selectivity and potency. One compound which has shown great selectivity and potency in vitro is <scene name='Sean_Swale/Human_Thrombin_Inhibitor/Inhibitor_65/1'>inhibitor 65</scene>.<ref> DOI: 10.1002/cmdc.201200292</ref>

----

===Phe-Pro-p-amidinobenzylamine===
An early experiment to find a better thrombin inhibitor yielded a structure that was able to bond to the P1 and P2 sites of Thrombin effectively. In 1996 Lilly research laboratories created D-Phe-Pro-p-amidinobenzylamine by making improvements on the previous structure D-Phe-Pro-Agmatine. The new compound they created bonded to thrombin 130x more than it did to trypsin (also a serine protease), and it was highly selective of thrombin over fibrinolytic enzymes which break down fibrin clots. The inhibitor bound with Thrombin at rates 26,000x greater than with plasmin,<ref> http://voices.yahoo.com/what-fibrinolytic-enzymes-6186058.html?cat=68</ref>, 170,000x greater than with t-Pa, and 400,000x greater than with urokinase.
[[Image:1996 inhibitor rates.png|center|600px|frame|Inhibitor 12 is the identical P1 and P2 sites of Inhibitor 65.(1996)<ref> M. R. Wiley, N. Y. Chirgadze, D. K. Clawson, T. J. Craft, D. S. GiffordMoore, N. D. Jones, J. L. Olkowski, L. C. Weir, G. F. Smith, Bioorg. Med. Chem. Lett. 1996, 6, 2387. http://www.sciencedirect.com/science/article/pii/0960894X96004428 </ref>]]
Its selectivity was gained by binding its nitrogens on the benzamidine group by hydrogen bonding to Asp 189, and by fitting its benzamidine benzene into a hydrophobic pocket with Ser 214-Glu 217 and Asp 189-Glu 192 on the other side. The proline residue is in another hydrophobic pocket made up of His 57, Tyr 60A, Leu 99, and Trp 60D. The rest of this structure is unimportant on review of inhibitor 65 because only the amidinobenzylamine which occupies R1 and the proline which occupies the R2 sit are the same residues on inhibitor 65.<ref> M. R. Wiley, N. Y. Chirgadze, D. K. Clawson, T. J. Craft, D. S. GiffordMoore, N. D. Jones, J. L. Olkowski, L. C. Weir, G. F. Smith, Bioorg. Med. Chem. Lett. 1996, 6, 2387. http://www.sciencedirect.com/science/article/pii/0960894X96004428 </ref>

----

===P3 and P4 of Inhibitor 65===
[[Image:Inhibitor 65.png|center|400px|frame|<ref> DOI: 10.1002/cmdc.201200292</ref> ]]
Inhibitor 65 additionally has a P4 sulfonyl group with a methoxy group at the end of the residue. It sits in tight VanderWaals structure with the surrounding residues Leu 99, Tyr 60A, Arg 97, Glu 97, and Asn 98.Additionally, the chlorine points to the carbonyl oxygen of Asn 98 and there is a weak Cl-π bond with Trp 215. For the P3 residue, there the backbone of asparagine forms and anti parallel beta sheet with Gly 216. The alkylated asparagine’s NH binds to water which then connects to Glu 192, and the NH of Gly 219 and Gly 216.
[[Image:Thrombin1.gif|left|frame|300px|a) Stereo view of the complete inhibitor structure provided with its electron density in the active site of thrombin. Thrombin is shown with its solvent- accessible surface. b) The P4 sulfonyl residue is located in the aryl binding pocket. The chlorine atom points to the carbonyl oxygen of Asn 98 and accommodates a position above the indole moiety of Trp 215. The methoxy group perfectly fills the upper niche of the S3/4 pocket. c) The P3 side chain is directed into the solvent, where its amide NH binds via a bridging water molecule to Glu 192, Gly 216 and Gly 219.<ref> DOI: 10.1002/cmdc.201200292</ref> ]]

</StructureSection>
This is the <scene name='Sean_Swale/Human_Thrombin_Inhibitor/Thrombin_active_site/2'>active site</scene> of thrombin

[[Image:1ppb-transparent.gif|right|500px|frame|Thrombin with serine residue visible.<ref>January 2002 Molecule of the Month by David Goodsell http://www.rcsb.org/pdb/101/motm.do?momID=25 </ref>]]

==References==
{{reflist}}

Sean Swale/Human Thrombin Inhibitor

2012-11-15T21:39:36Z

Sean Swale:

<StructureSection load='3utu' size='500' frame='false' align='right' |caption='Human Thrombin' scene=''>
<scene name='Sean_Swale/Human_Thrombin_Inhibitor/Active_site/1'>Total active site</scene>
===Reasons to develop another Thrombin Inhibitor===
Thrombin is a serine protease that cleaves fibrinogen to allow fibrin to form stringy networks that trap red blood cells to form clots. Thrombin is a serine protease because it cleaves fibrinogen with its serine residue. Thrombin when made by the body is tethered to blood vessels so that it cannot cause clots throughout the body causing strokes and heart attacks. Additionally, thrombin is only activated for a few seconds to limit the clotted area to the injured area<ref>January 2002 Molecule of the Month by David Goodsell http://www.rcsb.org/pdb/101/motm.do?momID=25 </ref>. However, when fibrin has accumulated at an injury site, sometimes it will break away and occlude a blood vessel which can cause stroke or heart attack. In order to prevent venous thrombosis, blood clots, after surgery or during dialysis when blood is in contact with artificial devices, Heparin is normally administered. Unfortunately Heparin is neutralized by plasma proteins in the blood, is less efficient for the inhibition of clot bound thrombin, and can trigger an enormous immune response. Antithrombotic drugs like Hirudin will be given if Heparin is not able to be tolerated or if the person receives regular dialysis. Hirudin administration require large doses to maintain proper inhibition of Thrombin which heavily taxes the body. Chemists have been working on designer drugs to increase selectivity and potency. One compound which has shown great selectivity and potency in vitro is <scene name='Sean_Swale/Human_Thrombin_Inhibitor/Inhibitor_65/1'>inhibitor 65</scene>.<ref> DOI: 10.1002/cmdc.201200292</ref>

----

===Phe-Pro-p-amidinobenzylamine===
An early experiment to find a better thrombin inhibitor yielded a structure that was able to bond to the P1 and P2 sites of Thrombin effectively. In 1996 Lilly research laboratories created D-Phe-Pro-p-amidinobenzylamine by making improvements on the previous structure D-Phe-Pro-Agmatine. The new compound they created bonded to thrombin 130x more than it did to trypsin (also a serine protease), and it was highly selective of thrombin over fibrinolytic enzymes which break down fibrin clots. The inhibitor bound with Thrombin at rates 26,000x greater than with plasmin,<ref> http://voices.yahoo.com/what-fibrinolytic-enzymes-6186058.html?cat=68</ref>, 170,000x greater than with t-Pa, and 400,000x greater than with urokinase.
[[Image:1996 inhibitor rates.png|center|600px|frame|Inhibitor 12 is the identical P1 and P2 sites of Inhibitor 65.(1996)<ref> M. R. Wiley, N. Y. Chirgadze, D. K. Clawson, T. J. Craft, D. S. GiffordMoore, N. D. Jones, J. L. Olkowski, L. C. Weir, G. F. Smith, Bioorg. Med. Chem. Lett. 1996, 6, 2387. http://www.sciencedirect.com/science/article/pii/0960894X96004428 </ref>]]
Its selectivity was gained by binding its nitrogens on the benzamidine group by hydrogen bonding to Asp 189, and by fitting its benzamidine benzene into a hydrophobic pocket with Ser 214-Glu 217 and Asp 189-Glu 192 on the other side. The proline residue is in another hydrophobic pocket made up of His 57, Tyr 60A, Leu 99, and Trp 60D. The rest of this structure is unimportant on review of inhibitor 65 because only the amidinobenzylamine which occupies R1 and the proline which occupies the R2 sit are the same residues on inhibitor 65.<ref> M. R. Wiley, N. Y. Chirgadze, D. K. Clawson, T. J. Craft, D. S. GiffordMoore, N. D. Jones, J. L. Olkowski, L. C. Weir, G. F. Smith, Bioorg. Med. Chem. Lett. 1996, 6, 2387. http://www.sciencedirect.com/science/article/pii/0960894X96004428 </ref>

----

===P3 and P4 of Inhibitor 65===
[[Image:Inhibitor 65.png|center|400px|frame|<ref> DOI: 10.1002/cmdc.201200292</ref> ]]
Inhibitor 65 additionally has a P4 sulfonyl group with a methoxy group at the end of the residue. It sits in tight VanderWaals structure with the surrounding residues Leu 99, Tyr 60A, Arg 97, Glu 97, and Asn 98.Additionally, the chlorine points to the carbonyl oxygen of Asn 98 and there is a weak Cl-π bond with Trp 215. For the P3 residue, there the backbone of asparagine forms and anti parallel beta sheet with Gly 216. The alkylated asparagine’s NH binds to water which then connects to Glu 192, and the NH of Gly 219 and Gly 216.
[[Image:Thrombin1.gif|left|frame|300px|a) Stereo view of the complete inhibitor structure provided with its electron density in the active site of thrombin. Thrombin is shown with its solvent- accessible surface. b) The P4 sulfonyl residue is located in the aryl binding pocket. The chlorine atom points to the carbonyl oxygen of Asn 98 and accommodates a position above the indole moiety of Trp 215. The methoxy group perfectly fills the upper niche of the S3/4 pocket. c) The P3 side chain is directed into the solvent, where its amide NH binds via a bridging water molecule to Glu 192, Gly 216 and Gly 219.<ref> DOI: 10.1002/cmdc.201200292</ref> ]]

</StructureSection>
This is the <scene name='Sean_Swale/Human_Thrombin_Inhibitor/Thrombin_active_site/2'>active site</scene> of thrombin

[[Image:1ppb-transparent.gif|right|500px|frame|Thrombin with serine residue visible.<ref>January 2002 Molecule of the Month by David Goodsell http://www.rcsb.org/pdb/101/motm.do?momID=25 </ref>]]

==References==
{{reflist}}

Sean Swale/Human Thrombin Inhibitor

2012-11-15T21:27:44Z

Sean Swale:

<StructureSection load='3utu' size='500' frame='false' align='right' |caption='Human Thrombin' scene=''>
<scene name='Sean_Swale/Human_Thrombin_Inhibitor/Active_site/1'>Total active site</scene>
===Reasons to develop another Thrombin Inhibitor===
Thrombin is a serine protease that cleaves fibrinogen to allow fibrin to form stringy networks that trap red blood cells to form clots. Thrombin is a serine protease because it cleaves fibrinogen with its serine residue. Thrombin when made by the body is tethered to blood vessels so that it cannot cause clots throughout the body causing strokes and heart attacks. Additionally, thrombin is only activated for a few seconds to limit the clotted area to the injured area<ref>January 2002 Molecule of the Month by David Goodsell http://www.rcsb.org/pdb/101/motm.do?momID=25 </ref>. However, when fibrin has accumulated at an injury site, sometimes it will break away and occlude a blood vessel which can cause stroke or heart attack. In order to prevent venous thrombosis, blood clots, after surgery or during dialysis when blood is in contact with artificial devices, Heparin is normally administered. Unfortunately Heparin is neutralized by plasma proteins in the blood, is less efficient for the inhibition of clot bound thrombin, and can trigger an enormous immune response. Antithrombotic drugs like Hirudin will be given if Heparin is not able to be tolerated or if the person receives regular dialysis. Hirudin administration require large doses to maintain proper inhibition of Thrombin which heavily taxes the body. Chemists have been working on designer drugs to increase selectivity and potency. One compound which has shown great selectivity and potency in vitro is inhibitor 65.<ref> DOI: 10.1002/cmdc.201200292</ref>

----

===Phe-Pro-p-amidinobenzylamine===
An early experiment to find a better thrombin inhibitor yielded a structure that was able to bond to the P1 and P2 sites of Thrombin effectively. In 1996 Lilly research laboratories created D-Phe-Pro-p-amidinobenzylamine by making improvements on the previous structure D-Phe-Pro-Agmatine. The new compound they created bonded to thrombin 130x more than it did to trypsin (also a serine protease), and it was highly selective of thrombin over fibrinolytic enzymes which break down fibrin clots. The inhibitor bound with Thrombin at rates 26,000x greater than with plasmin,<ref> http://voices.yahoo.com/what-fibrinolytic-enzymes-6186058.html?cat=68</ref>, 170,000x greater than with t-Pa, and 400,000x greater than with urokinase.
[[Image:1996 inhibitor rates.png|center|600px|frame|Inhibitor 12 is the identical P1 and P2 sites of Inhibitor 65.(1996)<ref> M. R. Wiley, N. Y. Chirgadze, D. K. Clawson, T. J. Craft, D. S. GiffordMoore, N. D. Jones, J. L. Olkowski, L. C. Weir, G. F. Smith, Bioorg. Med. Chem. Lett. 1996, 6, 2387. http://www.sciencedirect.com/science/article/pii/0960894X96004428 </ref>]]
Its selectivity was gained by binding its nitrogens on the benzamidine group by hydrogen bonding to Asp 189, and by fitting its benzamidine benzene into a hydrophobic pocket with Ser 214-Glu 217 and Asp 189-Glu 192 on the other side. The proline residue is in another hydrophobic pocket made up of His 57, Tyr 60A, Leu 99, and Trp 60D. The rest of this structure is unimportant on review of inhibitor 65 because only the amidinobenzylamine which occupies R1 and the proline which occupies the R2 sit are the same residues on inhibitor 65.<ref> M. R. Wiley, N. Y. Chirgadze, D. K. Clawson, T. J. Craft, D. S. GiffordMoore, N. D. Jones, J. L. Olkowski, L. C. Weir, G. F. Smith, Bioorg. Med. Chem. Lett. 1996, 6, 2387. http://www.sciencedirect.com/science/article/pii/0960894X96004428 </ref>

----

===P3 and P4 of Inhibitor 65===
[[Image:Inhibitor 65.png|center|400px|frame|<ref> DOI: 10.1002/cmdc.201200292</ref> ]]
Inhibitor 65 additionally has a P4 sulfonyl group with a methoxy group at the end of the residue. It sits in tight VanderWaals structure with the surrounding residues Leu 99, Tyr 60A, Arg 97, Glu 97, and Asn 98.Additionally, the chlorine points to the carbonyl oxygen of Asn 98 and there is a weak Cl-π bond with Trp 215. For the P3 residue, there the backbone of asparagine forms and anti parallel beta sheet with Gly 216. The alkylated asparagine’s NH binds to water which then connects to Glu 192, and the NH of Gly 219 and Gly 216.
[[Image:Thrombin1.gif|left|frame|300px|a) Stereo view of the complete inhibitor structure provided with its electron density in the active site of thrombin. Thrombin is shown with its solvent- accessible surface. b) The P4 sulfonyl residue is located in the aryl binding pocket. The chlorine atom points to the carbonyl oxygen of Asn 98 and accommodates a position above the indole moiety of Trp 215. The methoxy group perfectly fills the upper niche of the S3/4 pocket. c) The P3 side chain is directed into the solvent, where its amide NH binds via a bridging water molecule to Glu 192, Gly 216 and Gly 219.<ref> DOI: 10.1002/cmdc.201200292</ref> ]]

</StructureSection>
This is the <scene name='Sean_Swale/Human_Thrombin_Inhibitor/Thrombin_active_site/2'>active site</scene> of thrombin

[[Image:1ppb-transparent.gif|right|500px|frame|Thrombin with serine residue visible.<ref>January 2002 Molecule of the Month by David Goodsell http://www.rcsb.org/pdb/101/motm.do?momID=25 </ref>]]

==References==
{{reflist}}

Sean Swale/Human Thrombin Inhibitor

2012-11-15T21:22:15Z

Sean Swale:

<StructureSection load='3utu' size='500' frame='false' align='right' |caption='Human Thrombin' scene=''>
<scene name='Sean_Swale/Human_Thrombin_Inhibitor/Active_site/1'>Total active site</scene>
===Reasons to develop another Thrombin Inhibitor===
Thrombin is a serine protease that cleaves fibrinogen to allow fibrin to form stringy networks that trap red blood cells to form clots. Thrombin is a serine protease because it cleaves fibrinogen with its serine residue. Thrombin when made by the body is tethered to blood vessels so that it cannot cause clots throughout the body causing strokes and heart attacks. Additionally, thrombin is only activated for a few seconds to limit the clotted area to the injured area<ref>January 2002 Molecule of the Month by David Goodsell http://www.rcsb.org/pdb/101/motm.do?momID=25 </ref>. However, when fibrin has accumulated at an injury site, sometimes it will break away and occlude a blood vessel which can cause stroke or heart attack. In order to prevent venous thrombosis, blood clots, after surgery or during dialysis when blood is in contact with artificial devices, Heparin is normally administered. Unfortunately Heparin is neutralized by plasma proteins in the blood, is less efficient for the inhibition of clot bound thrombin, and can trigger an enormous immune response. Antithrombotic drugs like Hirudin will be given if Heparin is not able to be tolerated or if the person receives regular dialysis. Hirudin administration require large doses to maintain proper inhibition of Thrombin which heavily taxes the body. Chemists have been working on designer drugs to increase selectivity and potency. One compound which has shown great selectivity and potency in vitro is inhibitor 65.<ref> DOI: 10.1002/cmdc.201200292</ref>

----

===Phe-Pro-p-amidinobenzylamine===
An early experiment to find a better thrombin inhibitor yielded a structure that was able to bond to the P1 and P2 sites of Thrombin effectively. In 1996 Lilly research laboratories created D-Phe-Pro-p-amidinobenzylamine by making improvements on the previous structure D-Phe-Pro-Agmatine. The new compound they created bonded to thrombin 130x more than it did to trypsin (also a serine protease), and it was highly selective of thrombin over fibrinolytic enzymes which break down fibrin clots. The inhibitor bound with Thrombin at rates 26,000x greater than with plasmin,<ref> http://voices.yahoo.com/what-fibrinolytic-enzymes-6186058.html?cat=68</ref>, 170,000x greater than with t-Pa, and 400,000x greater than with urokinase.
[[Image:1996 inhibitor rates.png|center|600px|frame|<ref> M. R. Wiley, N. Y. Chirgadze, D. K. Clawson, T. J. Craft, D. S. GiffordMoore, N. D. Jones, J. L. Olkowski, L. C. Weir, G. F. Smith, Bioorg. Med. Chem. Lett. 1996, 6, 2387. http://www.sciencedirect.com/science/article/pii/0960894X96004428 </ref>]]
Its selectivity was gained by binding its nitrogens on the benzamidine group by hydrogen bonding to Asp 189, and by fitting its benzamidine benzene into a hydrophobic pocket with Ser 214-Glu 217 and Asp 189-Glu 192 on the other side. The proline residue is in another hydrophobic pocket made up of His 57, Tyr 60A, Leu 99, and Trp 60D. The rest of this structure is unimportant on review of inhibitor 65 because only the amidinobenzylamine which occupies R1 and the proline which occupies the R2 sit are the same residues on inhibitor 65.<ref> M. R. Wiley, N. Y. Chirgadze, D. K. Clawson, T. J. Craft, D. S. GiffordMoore, N. D. Jones, J. L. Olkowski, L. C. Weir, G. F. Smith, Bioorg. Med. Chem. Lett. 1996, 6, 2387. http://www.sciencedirect.com/science/article/pii/0960894X96004428 </ref>

----

===P3 and P4 of Inhibitor 65===
[[Image:Inhibitor 65.png|center|400px|frame|<ref> DOI: 10.1002/cmdc.201200292</ref> ]]
Inhibitor 65 additionally has a P4 sulfonyl group with a methoxy group at the end of the residue. It sits in tight VanderWaals structure with the surrounding residues Leu 99, Tyr 60A, Arg 97, Glu 97, and Asn 98.Additionally, the chlorine points to the carbonyl oxygen of Asn 98 and there is a weak Cl-π bond with Trp 215. For the P3 residue, there the backbone of asparagine forms and anti parallel beta sheet with Gly 216. The alkylated asparagine’s NH binds to water which then connects to Glu 192, and the NH of Gly 219 and Gly 216.
[[Image:Thrombin1.gif|left|frame|300px|a) Stereo view of the complete inhibitor structure provided with its electron density in the active site of thrombin. Thrombin is shown with its solvent- accessible surface. b) The P4 sulfonyl residue is located in the aryl binding pocket. The chlorine atom points to the carbonyl oxygen of Asn 98 and accommodates a position above the indole moiety of Trp 215. The methoxy group perfectly fills the upper niche of the S3/4 pocket. c) The P3 side chain is directed into the solvent, where its amide NH binds via a bridging water molecule to Glu 192, Gly 216 and Gly 219.<ref> DOI: 10.1002/cmdc.201200292</ref> ]]

</StructureSection>
This is the <scene name='Sean_Swale/Human_Thrombin_Inhibitor/Thrombin_active_site/2'>active site</scene> of thrombin

[[Image:1ppb-transparent.gif|right|500px|frame|Thrombin with serine residue visible.<ref>January 2002 Molecule of the Month by David Goodsell http://www.rcsb.org/pdb/101/motm.do?momID=25 </ref>]]

==References==
{{reflist}}

Sean Swale/Human Thrombin Inhibitor

2012-11-15T21:18:41Z

Sean Swale:

<StructureSection load='3utu' size='500' frame='false' align='right' |caption='Human Thrombin' scene=''>
<scene name='Sean_Swale/Human_Thrombin_Inhibitor/Active_site/1'>Total active site</scene>
===Reasons to develop another Thrombin Inhibitor===
Thrombin is a serine protease that cleaves fibrinogen to allow fibrin to form stringy networks that trap red blood cells to form clots. Thrombin is a serine protease because it cleaves fibrinogen with its serine residue. Thrombin when made by the body is tethered to blood vessels so that it cannot cause clots throughout the body causing strokes and heart attacks. Additionally, thrombin is only activated for a few seconds to limit the clotted area to the injured area<ref>January 2002 Molecule of the Month by David Goodsell http://www.rcsb.org/pdb/101/motm.do?momID=25 </ref>. However, when fibrin has accumulated at an injury site, sometimes it will break away and occlude a blood vessel which can cause stroke or heart attack. In order to prevent venous thrombosis, blood clots, after surgery or during dialysis when blood is in contact with artificial devices, Heparin is normally administered. Unfortunately Heparin is neutralized by plasma proteins in the blood, is less efficient for the inhibition of clot bound thrombin, and can trigger an enormous immune response. Antithrombotic drugs like Hirudin will be given if Heparin is not able to be tolerated or if the person receives regular dialysis. Hirudin administration require large doses to maintain proper inhibition of Thrombin which heavily taxes the body. Chemists have been working on designer drugs to increase selectivity and potency. One compound which has shown great selectivity and potency in vitro is inhibitor 65.<ref> DOI: 10.1002/cmdc.201200292</ref>

----

===Phe-Pro-p-amidinobenzylamine===
An early experiment to find a better thrombin inhibitor yielded a structure that was able to bond to the P1 and P2 sites of Thrombin effectively. In 1996 Lilly research laboratories created D-Phe-Pro-p-amidinobenzylamine by making improvements on the previous structure D-Phe-Pro-Agmatine. The new compound they created bonded to thrombin 130x more than it did to trypsin (also a serine protease), and it was highly selective of thrombin over fibrinolytic enzymes which break down fibrin clots. The inhibitor bound with Thrombin at rates 26,000x greater than with plasmin,<ref> http://voices.yahoo.com/what-fibrinolytic-enzymes-6186058.html?cat=68</ref>, 170,000x greater than with t-Pa, and 400,000x greater than with urokinase.
[[Image:1996 inhibitor rates.png|center|600px]]
Its selectivity was gained by binding its nitrogens on the benzamidine group by hydrogen bonding to Asp 189, and by fitting its benzamidine benzene into a hydrophobic pocket with Ser 214-Glu 217 and Asp 189-Glu 192 on the other side. The proline residue is in another hydrophobic pocket made up of His 57, Tyr 60A, Leu 99, and Trp 60D. The rest of this structure is unimportant on review of inhibitor 65 because only the amidinobenzylamine which occupies R1 and the proline which occupies the R2 sit are the same residues on inhibitor 65.<ref> M. R. Wiley, N. Y. Chirgadze, D. K. Clawson, T. J. Craft, D. S. GiffordMoore, N. D. Jones, J. L. Olkowski, L. C. Weir, G. F. Smith, Bioorg. Med. Chem. Lett. 1996, 6, 2387. http://www.sciencedirect.com/science/article/pii/0960894X96004428 </ref>

----

===P3 and P4 of Inhibitor 65===
[[Image:Inhibitor 65.png|center|400px]]
Inhibitor 65 additionally has a P4 sulfonyl group with a methoxy group at the end of the residue. It sits in tight VanderWaals structure with the surrounding residues Leu 99, Tyr 60A, Arg 97, Glu 97, and Asn 98.Additionally, the chlorine points to the carbonyl oxygen of Asn 98 and there is a weak Cl-π bond with Trp 215. For the P3 residue, there the backbone of asparagine forms and anti parallel beta sheet with Gly 216. The alkylated asparagine’s NH binds to water which then connects to Glu 192, and the NH of Gly 219 and Gly 216.
[[Image:Thrombin1.gif|left|frame|300px|a) Stereo view of the complete inhibitor structure provided with its electron density in the active site of thrombin. Thrombin is shown with its solvent- accessible surface. b) The P4 sulfonyl residue is located in the aryl binding pocket. The chlorine atom points to the carbonyl oxygen of Asn 98 and accommodates a position above the indole moiety of Trp 215. The methoxy group perfectly fills the upper niche of the S3/4 pocket. c) The P3 side chain is directed into the solvent, where its amide NH binds via a bridging water molecule to Glu 192, Gly 216 and Gly 219.]]

</StructureSection>
This is the <scene name='Sean_Swale/Human_Thrombin_Inhibitor/Thrombin_active_site/2'>active site</scene> of thrombin

[[Image:1ppb-transparent.gif|right|500px]]

==References==
{{reflist}}

Sean Swale/Human Thrombin Inhibitor

2012-11-15T21:17:25Z

Sean Swale:

<StructureSection load='3utu' size='500' frame='false' align='right' |caption='Human Thrombin' scene=''>
<scene name='Sean_Swale/Human_Thrombin_Inhibitor/Active_site/1'>Total active site</scene>
===Reasons to develop another Thrombin Inhibitor===
Thrombin is a serine protease that cleaves fibrinogen to allow fibrin to form stringy networks that trap red blood cells to form clots. Thrombin is a serine protease because it cleaves fibrinogen with its serine residue. Thrombin when made by the body is tethered to blood vessels so that it cannot cause clots throughout the body causing strokes and heart attacks. Additionally, thrombin is only activated for a few seconds to limit the clotted area to the injured area<ref>January 2002 Molecule of the Month by David Goodsell http://www.rcsb.org/pdb/101/motm.do?momID=25 </ref>. However, when fibrin has accumulated at an injury site, sometimes it will break away and occlude a blood vessel which can cause stroke or heart attack. In order to prevent venous thrombosis, blood clots, after surgery or during dialysis when blood is in contact with artificial devices, Heparin is normally administered. Unfortunately Heparin is neutralized by plasma proteins in the blood, is less efficient for the inhibition of clot bound thrombin, and can trigger an enormous immune response. Antithrombotic drugs like Hirudin will be given if Heparin is not able to be tolerated or if the person receives regular dialysis. Hirudin administration require large doses to maintain proper inhibition of Thrombin which heavily taxes the body. Chemists have been working on designer drugs to increase selectivity and potency. One compound which has shown great selectivity and potency in vitro is inhibitor 65.<ref> DOI: 10.1002/cmdc.201200292</ref>

----

===Phe-Pro-p-amidinobenzylamine===
An early experiment to find a better thrombin inhibitor yielded a structure that was able to bond to the P1 and P2 sites of Thrombin effectively. In 1996 Lilly research laboratories created D-Phe-Pro-p-amidinobenzylamine by making improvements on the previous structure D-Phe-Pro-Agmatine. The new compound they created bonded to thrombin 130x more than it did to trypsin (also a serine protease), and it was highly selective of thrombin over fibrinolytic enzymes which break down fibrin clots. The inhibitor bound with Thrombin at rates 26,000x greater than with plasmin,<ref> http://voices.yahoo.com/what-fibrinolytic-enzymes-6186058.html?cat=68</ref>, 170,000x greater than with t-Pa, and 400,000x greater than with urokinase.
[[Image:1996 inhibitor rates.png|center|600px]]
Its selectivity was gained by binding its nitrogens on the benzamidine group by hydrogen bonding to Asp 189, and by fitting its benzamidine benzene into a hydrophobic pocket with Ser 214-Glu 217 and Asp 189-Glu 192 on the other side. The proline residue is in another hydrophobic pocket made up of His 57, Tyr 60A, Leu 99, and Trp 60D. The rest of this structure is unimportant on review of inhibitor 65 because only the amidinobenzylamine which occupies R1 and the proline which occupies the R2 sit are the same residues on inhibitor 65.<ref> M. R. Wiley, N. Y. Chirgadze, D. K. Clawson, T. J. Craft, D. S. GiffordMoore, N. D. Jones, J. L. Olkowski, L. C. Weir, G. F. Smith, Bioorg. Med. Chem. Lett. 1996, 6, 2387. http://www.sciencedirect.com/science/article/pii/0960894X96004428 </ref>

----

===P3 and P4 of Inhibitor 65===
[[Image:Inhibitor 65.png|center|400px]]
Inhibitor 65 additionally has a P4 sulfonyl group with a methoxy group at the end of the residue. It sits in tight VanderWaals structure with the surrounding residues Leu 99, Tyr 60A, Arg 97, Glu 97, and Asn 98.Additionally, the chlorine points to the carbonyl oxygen of Asn 98 and there is a weak Cl-π bond with Trp 215. For the P3 residue, there the backbone of asparagine forms and anti parallel beta sheet with Gly 216. The alkylated asparagine’s NH binds to water which then connects to Glu 192, and the NH of Gly 219 and Gly 216.
[[Image:Thrombin1.gif|center|300px|a) Stereo view of the complete inhibitor structure provided with its electron density in the active site of thrombin. Thrombin is shown with its solvent- accessible surface. b) The P4 sulfonyl residue is located in the aryl binding pocket. The chlorine atom points to the carbonyl oxygen of Asn 98 and accommodates a position above the indole moiety of Trp 215. The methoxy group perfectly fills the upper niche of the S3/4 pocket. c) The P3 side chain is directed into the solvent, where its amide NH binds via a bridging water molecule to Glu 192, Gly 216 and Gly 219.]]

</StructureSection>
This is the <scene name='Sean_Swale/Human_Thrombin_Inhibitor/Thrombin_active_site/2'>active site</scene> of thrombin

[[Image:1ppb-transparent.gif|right|500px]]

==References==
{{reflist}}

Sean Swale/Human Thrombin Inhibitor

2012-11-15T21:14:50Z

Sean Swale:

<StructureSection load='3utu' size='500' frame='false' align='right' |caption='Human Thrombin' scene=''>
<scene name='Sean_Swale/Human_Thrombin_Inhibitor/Active_site/1'>Total active site</scene>
===Reasons to develop another Thrombin Inhibitor===
Thrombin is a serine protease that cleaves fibrinogen to allow fibrin to form stringy networks that trap red blood cells to form clots. Thrombin is a serine protease because it cleaves fibrinogen with its serine residue. Thrombin when made by the body is tethered to blood vessels so that it cannot cause clots throughout the body causing strokes and heart attacks. Additionally, thrombin is only activated for a few seconds to limit the clotted area to the injured area<ref>January 2002 Molecule of the Month by David Goodsell http://www.rcsb.org/pdb/101/motm.do?momID=25 </ref>. However, when fibrin has accumulated at an injury site, sometimes it will break away and occlude a blood vessel which can cause stroke or heart attack. In order to prevent venous thrombosis, blood clots, after surgery or during dialysis when blood is in contact with artificial devices, Heparin is normally administered. Unfortunately Heparin is neutralized by plasma proteins in the blood, is less efficient for the inhibition of clot bound thrombin, and can trigger an enormous immune response. Antithrombotic drugs like Hirudin will be given if Heparin is not able to be tolerated or if the person receives regular dialysis. Hirudin administration require large doses to maintain proper inhibition of Thrombin which heavily taxes the body. Chemists have been working on designer drugs to increase selectivity and potency. One compound which has shown great selectivity and potency in vitro is inhibitor 65.<ref> DOI: 10.1002/cmdc.201200292</ref>

----

===Phe-Pro-p-amidinobenzylamine===
An early experiment to find a better thrombin inhibitor yielded a structure that was able to bond to the P1 and P2 sites of Thrombin effectively. In 1996 Lilly research laboratories created D-Phe-Pro-p-amidinobenzylamine by making improvements on the previous structure D-Phe-Pro-Agmatine. The new compound they created bonded to thrombin 130x more than it did to trypsin (also a serine protease), and it was highly selective of thrombin over fibrinolytic enzymes which break down fibrin clots. The inhibitor bound with Thrombin at rates 26,000x greater than with plasmin,<ref> http://voices.yahoo.com/what-fibrinolytic-enzymes-6186058.html?cat=68</ref>, 170,000x greater than with t-Pa, and 400,000x greater than with urokinase.
[[Image:1996 inhibitor rates.png|center|600px]]
Its selectivity was gained by binding its nitrogens on the benzamidine group by hydrogen bonding to Asp 189, and by fitting its benzamidine benzene into a hydrophobic pocket with Ser 214-Glu 217 and Asp 189-Glu 192 on the other side. The proline residue is in another hydrophobic pocket made up of His 57, Tyr 60A, Leu 99, and Trp 60D. The rest of this structure is unimportant on review of inhibitor 65 because only the amidinobenzylamine which occupies R1 and the proline which occupies the R2 sit are the same residues on inhibitor 65.<ref> M. R. Wiley, N. Y. Chirgadze, D. K. Clawson, T. J. Craft, D. S. GiffordMoore, N. D. Jones, J. L. Olkowski, L. C. Weir, G. F. Smith, Bioorg. Med. Chem. Lett. 1996, 6, 2387. http://www.sciencedirect.com/science/article/pii/0960894X96004428 </ref>

----

===P3 and P4 of Inhibitor 65===
[[Image:Inhibitor 65.png|center|400px]]
Inhibitor 65 additionally has a P4 sulfonyl group with a methoxy group at the end of the residue. It sits in tight VanderWaals structure with the surrounding residues Leu 99, Tyr 60A, Arg 97, Glu 97, and Asn 98.Additionally, the chlorine points to the carbonyl oxygen of Asn 98 and there is a weak Cl-π bond with Trp 215. For the P3 residue, there the backbone of asparagine forms and anti parallel beta sheet with Gly 216. The alkylated asparagine’s NH binds to water which then connects to Glu 192, and the NH of Gly 219 and Gly 216.
[[Image:Thrombin1.gif|center|400px]]
</StructureSection>
This is the <scene name='Sean_Swale/Human_Thrombin_Inhibitor/Thrombin_active_site/2'>active site</scene> of thrombin

[[Image:1ppb-transparent.gif|right|500px]]

==References==
{{reflist}}

File:Thrombin1.gif

2012-11-15T21:14:06Z

Sean Swale: uploaded a new version of "Image:Thrombin1.gif": Reverted to version as of 01:31, 9 November 2012

Sean Swale/Human Thrombin Inhibitor

2012-11-15T21:13:32Z

Sean Swale:

<StructureSection load='3utu' size='500' frame='false' align='right' |caption='Human Thrombin' scene=''>
<scene name='Sean_Swale/Human_Thrombin_Inhibitor/Active_site/1'>Total active site</scene>
===Reasons to develop another Thrombin Inhibitor===
Thrombin is a serine protease that cleaves fibrinogen to allow fibrin to form stringy networks that trap red blood cells to form clots. Thrombin is a serine protease because it cleaves fibrinogen with its serine residue. Thrombin when made by the body is tethered to blood vessels so that it cannot cause clots throughout the body causing strokes and heart attacks. Additionally, thrombin is only activated for a few seconds to limit the clotted area to the injured area<ref>January 2002 Molecule of the Month by David Goodsell http://www.rcsb.org/pdb/101/motm.do?momID=25 </ref>. However, when fibrin has accumulated at an injury site, sometimes it will break away and occlude a blood vessel which can cause stroke or heart attack. In order to prevent venous thrombosis, blood clots, after surgery or during dialysis when blood is in contact with artificial devices, Heparin is normally administered. Unfortunately Heparin is neutralized by plasma proteins in the blood, is less efficient for the inhibition of clot bound thrombin, and can trigger an enormous immune response. Antithrombotic drugs like Hirudin will be given if Heparin is not able to be tolerated or if the person receives regular dialysis. Hirudin administration require large doses to maintain proper inhibition of Thrombin which heavily taxes the body. Chemists have been working on designer drugs to increase selectivity and potency. One compound which has shown great selectivity and potency in vitro is inhibitor 65.<ref> DOI: 10.1002/cmdc.201200292</ref>

----

===Phe-Pro-p-amidinobenzylamine===
An early experiment to find a better thrombin inhibitor yielded a structure that was able to bond to the P1 and P2 sites of Thrombin effectively. In 1996 Lilly research laboratories created D-Phe-Pro-p-amidinobenzylamine by making improvements on the previous structure D-Phe-Pro-Agmatine. The new compound they created bonded to thrombin 130x more than it did to trypsin (also a serine protease), and it was highly selective of thrombin over fibrinolytic enzymes which break down fibrin clots. The inhibitor bound with Thrombin at rates 26,000x greater than with plasmin,<ref> http://voices.yahoo.com/what-fibrinolytic-enzymes-6186058.html?cat=68</ref>, 170,000x greater than with t-Pa, and 400,000x greater than with urokinase.
[[Image:1996 inhibitor rates.png|center|600px]]
Its selectivity was gained by binding its nitrogens on the benzamidine group by hydrogen bonding to Asp 189, and by fitting its benzamidine benzene into a hydrophobic pocket with Ser 214-Glu 217 and Asp 189-Glu 192 on the other side. The proline residue is in another hydrophobic pocket made up of His 57, Tyr 60A, Leu 99, and Trp 60D. The rest of this structure is unimportant on review of inhibitor 65 because only the amidinobenzylamine which occupies R1 and the proline which occupies the R2 sit are the same residues on inhibitor 65.<ref> M. R. Wiley, N. Y. Chirgadze, D. K. Clawson, T. J. Craft, D. S. GiffordMoore, N. D. Jones, J. L. Olkowski, L. C. Weir, G. F. Smith, Bioorg. Med. Chem. Lett. 1996, 6, 2387. http://www.sciencedirect.com/science/article/pii/0960894X96004428 </ref>

----

===P3 and P4 of Inhibitor 65===
[[Image:Inhibitor 65.png|center|400px]]
Inhibitor 65 additionally has a P4 sulfonyl group with a methoxy group at the end of the residue. It sits in tight VanderWaals structure with the surrounding residues Leu 99, Tyr 60A, Arg 97, Glu 97, and Asn 98.Additionally, the chlorine points to the carbonyl oxygen of Asn 98 and there is a weak Cl-π bond with Trp 215. For the P3 residue, there the backbone of asparagine forms and anti parallel beta sheet with Gly 216. The alkylated asparagine’s NH binds to water which then connects to Glu 192, and the NH of Gly 219 and Gly 216.
[[Image:Thrombin1.png|center|400px]]
</StructureSection>
This is the <scene name='Sean_Swale/Human_Thrombin_Inhibitor/Thrombin_active_site/2'>active site</scene> of thrombin

[[Image:1ppb-transparent.gif|right|500px]]

==References==
{{reflist}}

Sean Swale/Human Thrombin Inhibitor

2012-11-15T21:08:11Z

Sean Swale:

<StructureSection load='3utu' size='500' frame='false' align='right' |caption='Human Thrombin' scene=''>
<scene name='Sean_Swale/Human_Thrombin_Inhibitor/Active_site/1'>Total active site</scene>
===Reasons to develop another Thrombin Inhibitor===
Thrombin is a serine protease that cleaves fibrinogen to allow fibrin to form stringy networks that trap red blood cells to form clots. Thrombin is a serine protease because it cleaves fibrinogen with its serine residue. Thrombin when made by the body is tethered to blood vessels so that it cannot cause clots throughout the body causing strokes and heart attacks. Additionally, thrombin is only activated for a few seconds to limit the clotted area to the injured area<ref>January 2002 Molecule of the Month by David Goodsell http://www.rcsb.org/pdb/101/motm.do?momID=25 </ref>. However, when fibrin has accumulated at an injury site, sometimes it will break away and occlude a blood vessel which can cause stroke or heart attack. In order to prevent venous thrombosis, blood clots, after surgery or during dialysis when blood is in contact with artificial devices, Heparin is normally administered. Unfortunately Heparin is neutralized by plasma proteins in the blood, is less efficient for the inhibition of clot bound thrombin, and can trigger an enormous immune response. Antithrombotic drugs like Hirudin will be given if Heparin is not able to be tolerated or if the person receives regular dialysis. Hirudin administration require large doses to maintain proper inhibition of Thrombin which heavily taxes the body. Chemists have been working on designer drugs to increase selectivity and potency. One compound which has shown great selectivity and potency in vitro is inhibitor 65.<ref> DOI: 10.1002/cmdc.201200292</ref>

----

===Phe-Pro-p-amidinobenzylamine===
An early experiment to find a better thrombin inhibitor yielded a structure that was able to bond to the P1 and P2 sites of Thrombin effectively. In 1996 Lilly research laboratories created D-Phe-Pro-p-amidinobenzylamine by making improvements on the previous structure D-Phe-Pro-Agmatine. The new compound they created bonded to thrombin 130x more than it did to trypsin (also a serine protease), and it was highly selective of thrombin over fibrinolytic enzymes which break down fibrin clots. The inhibitor bound with Thrombin at rates 26,000x greater than with plasmin,<ref> http://voices.yahoo.com/what-fibrinolytic-enzymes-6186058.html?cat=68</ref>, 170,000x greater than with t-Pa, and 400,000x greater than with urokinase.
[[Image:1996 inhibitor rates.png|center|600px]]
Its selectivity was gained by binding its nitrogens on the benzamidine group by hydrogen bonding to Asp 189, and by fitting its benzamidine benzene into a hydrophobic pocket with Ser 214-Glu 217 and Asp 189-Glu 192 on the other side. The proline residue is in another hydrophobic pocket made up of His 57, Tyr 60A, Leu 99, and Trp 60D. The rest of this structure is unimportant on review of inhibitor 65 because only the amidinobenzylamine which occupies R1 and the proline which occupies the R2 sit are the same residues on inhibitor 65.<ref> M. R. Wiley, N. Y. Chirgadze, D. K. Clawson, T. J. Craft, D. S. GiffordMoore, N. D. Jones, J. L. Olkowski, L. C. Weir, G. F. Smith, Bioorg. Med. Chem. Lett. 1996, 6, 2387. http://www.sciencedirect.com/science/article/pii/0960894X96004428 </ref>

----

===P3 and P4 of Inhibitor 65===
[[Image:Inhibitor 65.png|center|400px]]
Inhibitor 65 additionally has a P4 sulfonyl group with a methoxy group at the end of the residue. It sits in tight VanderWaals structure with the surrounding residues Leu 99, Tyr 60A, Arg 97, Glu 97, and Asn 98.Additionally, the chlorine points to the carbonyl oxygen of Asn 98 and there is a weak Cl-π bond with Trp 215. For the P3 residue, there the backbone of asparagine forms and anti parallel beta sheet with Gly 216. The alkylated asparagine’s NH binds to water which then connects to Glu 192, and the NH of Gly 219 and Gly 216.
</StructureSection>
This is the <scene name='Sean_Swale/Human_Thrombin_Inhibitor/Thrombin_active_site/2'>active site</scene> of thrombin

[[Image:1ppb-transparent.gif|right|500px]]

==References==
{{reflist}}

Sean Swale/Human Thrombin Inhibitor

2012-11-15T21:07:13Z

Sean Swale:

<StructureSection load='3utu' size='500' frame='false' align='right' |caption='Human Thrombin' scene=''>
<scene name='Sean_Swale/Human_Thrombin_Inhibitor/Active_site/1'>Total active site</scene>
===Reasons to develop another Thrombin Inhibitor===
Thrombin is a serine protease that cleaves fibrinogen to allow fibrin to form stringy networks that trap red blood cells to form clots. Thrombin is a serine protease because it cleaves fibrinogen with its serine residue. Thrombin when made by the body is tethered to blood vessels so that it cannot cause clots throughout the body causing strokes and heart attacks. Additionally, thrombin is only activated for a few seconds to limit the clotted area to the injured area<ref>January 2002 Molecule of the Month by David Goodsell http://www.rcsb.org/pdb/101/motm.do?momID=25 </ref>. However, when fibrin has accumulated at an injury site, sometimes it will break away and occlude a blood vessel which can cause stroke or heart attack. In order to prevent venous thrombosis, blood clots, after surgery or during dialysis when blood is in contact with artificial devices, Heparin is normally administered. Unfortunately Heparin is neutralized by plasma proteins in the blood, is less efficient for the inhibition of clot bound thrombin, and can trigger an enormous immune response. Antithrombotic drugs like Hirudin will be given if Heparin is not able to be tolerated or if the person receives regular dialysis. Hirudin administration require large doses to maintain proper inhibition of Thrombin which heavily taxes the body. Chemists have been working on designer drugs to increase selectivity and potency. One compound which has shown great selectivity and potency in vitro is inhibitor 65.<ref> DOI: 10.1002/cmdc.201200292</ref>
===Phe-Pro-p-amidinobenzylamine===
An early experiment to find a better thrombin inhibitor yielded a structure that was able to bond to the P1 and P2 sites of Thrombin effectively. In 1996 Lilly research laboratories created D-Phe-Pro-p-amidinobenzylamine by making improvements on the previous structure D-Phe-Pro-Agmatine. The new compound they created bonded to thrombin 130x more than it did to trypsin (also a serine protease), and it was highly selective of thrombin over fibrinolytic enzymes which break down fibrin clots. The inhibitor bound with Thrombin at rates 26,000x greater than with plasmin,<ref> http://voices.yahoo.com/what-fibrinolytic-enzymes-6186058.html?cat=68</ref>, 170,000x greater than with t-Pa, and 400,000x greater than with urokinase.
[[Image:1996 inhibitor rates.png|center|400px]]

----

Its selectivity was gained by binding its nitrogens on the benzamidine group by hydrogen bonding to Asp 189, and by fitting its benzamidine benzene into a hydrophobic pocket with Ser 214-Glu 217 and Asp 189-Glu 192 on the other side. The proline residue is in another hydrophobic pocket made up of His 57, Tyr 60A, Leu 99, and Trp 60D. The rest of this structure is unimportant on review of inhibitor 65 because only the amidinobenzylamine which occupies R1 and the proline which occupies the R2 sit are the same residues on inhibitor 65.<ref> M. R. Wiley, N. Y. Chirgadze, D. K. Clawson, T. J. Craft, D. S. GiffordMoore, N. D. Jones, J. L. Olkowski, L. C. Weir, G. F. Smith, Bioorg. Med. Chem. Lett. 1996, 6, 2387. http://www.sciencedirect.com/science/article/pii/0960894X96004428 </ref>

===P3 and P4 of Inhibitor 65===
[[Image:Inhibitor 65.png|center|400px]]
Inhibitor 65 additionally has a P4 sulfonyl group with a methoxy group at the end of the residue. It sits in tight VanderWaals structure with the surrounding residues Leu 99, Tyr 60A, Arg 97, Glu 97, and Asn 98.Additionally, the chlorine points to the carbonyl oxygen of Asn 98 and there is a weak Cl-π bond with Trp 215. For the P3 residue, there the backbone of asparagine forms and anti parallel beta sheet with Gly 216. The alkylated asparagine’s NH binds to water which then connects to Glu 192, and the NH of Gly 219 and Gly 216.
</StructureSection>
This is the <scene name='Sean_Swale/Human_Thrombin_Inhibitor/Thrombin_active_site/2'>active site</scene> of thrombin

[[Image:1ppb-transparent.gif|right|500px]]

==References==
{{reflist}}

Sean Swale/Human Thrombin Inhibitor

2012-11-15T21:06:27Z

Sean Swale:

<StructureSection load='3utu' size='500' frame='false' align='right' |caption='Human Thrombin' scene=''>
<scene name='Sean_Swale/Human_Thrombin_Inhibitor/Active_site/1'>Total active site</scene>
===Reasons to develop another Thrombin Inhibitor===
Thrombin is a serine protease that cleaves fibrinogen to allow fibrin to form stringy networks that trap red blood cells to form clots. Thrombin is a serine protease because it cleaves fibrinogen with its serine residue. Thrombin when made by the body is tethered to blood vessels so that it cannot cause clots throughout the body causing strokes and heart attacks. Additionally, thrombin is only activated for a few seconds to limit the clotted area to the injured area<ref>January 2002 Molecule of the Month by David Goodsell http://www.rcsb.org/pdb/101/motm.do?momID=25 </ref>. However, when fibrin has accumulated at an injury site, sometimes it will break away and occlude a blood vessel which can cause stroke or heart attack. In order to prevent venous thrombosis, blood clots, after surgery or during dialysis when blood is in contact with artificial devices, Heparin is normally administered. Unfortunately Heparin is neutralized by plasma proteins in the blood, is less efficient for the inhibition of clot bound thrombin, and can trigger an enormous immune response. Antithrombotic drugs like Hirudin will be given if Heparin is not able to be tolerated or if the person receives regular dialysis. Hirudin administration require large doses to maintain proper inhibition of Thrombin which heavily taxes the body. Chemists have been working on designer drugs to increase selectivity and potency. One compound which has shown great selectivity and potency in vitro is inhibitor 65.<ref> DOI: 10.1002/cmdc.201200292</ref>
===Phe-Pro-p-amidinobenzylamine===
An early experiment to find a better thrombin inhibitor yielded a structure that was able to bond to the P1 and P2 sites of Thrombin effectively. In 1996 Lilly research laboratories created D-Phe-Pro-p-amidinobenzylamine by making improvements on the previous structure D-Phe-Pro-Agmatine. The new compound they created bonded to thrombin 130x more than it did to trypsin (also a serine protease), and it was highly selective of thrombin over fibrinolytic enzymes which break down fibrin clots. The inhibitor bound with Thrombin at rates 26,000x greater than with plasmin,<ref> http://voices.yahoo.com/what-fibrinolytic-enzymes-6186058.html?cat=68</ref>, 170,000x greater than with t-Pa, and 400,000x greater than with urokinase.
[[Image:1996 inhibitor rates.png|center|200px]]

----

Its selectivity was gained by binding its nitrogens on the benzamidine group by hydrogen bonding to Asp 189, and by fitting its benzamidine benzene into a hydrophobic pocket with Ser 214-Glu 217 and Asp 189-Glu 192 on the other side. The proline residue is in another hydrophobic pocket made up of His 57, Tyr 60A, Leu 99, and Trp 60D. The rest of this structure is unimportant on review of inhibitor 65 because only the amidinobenzylamine which occupies R1 and the proline which occupies the R2 sit are the same residues on inhibitor 65.<ref> M. R. Wiley, N. Y. Chirgadze, D. K. Clawson, T. J. Craft, D. S. GiffordMoore, N. D. Jones, J. L. Olkowski, L. C. Weir, G. F. Smith, Bioorg. Med. Chem. Lett. 1996, 6, 2387. http://www.sciencedirect.com/science/article/pii/0960894X96004428 </ref>

===P3 and P4 of Inhibitor 65===
[[Image:Inhibitor 65.png|center 200]]
Inhibitor 65 additionally has a P4 sulfonyl group with a methoxy group at the end of the residue. It sits in tight VanderWaals structure with the surrounding residues Leu 99, Tyr 60A, Arg 97, Glu 97, and Asn 98.Additionally, the chlorine points to the carbonyl oxygen of Asn 98 and there is a weak Cl-π bond with Trp 215. For the P3 residue, there the backbone of asparagine forms and anti parallel beta sheet with Gly 216. The alkylated asparagine’s NH binds to water which then connects to Glu 192, and the NH of Gly 219 and Gly 216.
</StructureSection>
This is the <scene name='Sean_Swale/Human_Thrombin_Inhibitor/Thrombin_active_site/2'>active site</scene> of thrombin

[[Image:1ppb-transparent.gif|right|500px]]

==References==
{{reflist}}

Sean Swale/Human Thrombin Inhibitor

2012-11-15T21:04:13Z

Sean Swale:

<StructureSection load='3utu' size='500' frame='false' align='right' |caption='Human Thrombin' scene=''>
<scene name='Sean_Swale/Human_Thrombin_Inhibitor/Active_site/1'>Total active site</scene>
===Reasons to develop another Thrombin Inhibitor===
Thrombin is a serine protease that cleaves fibrinogen to allow fibrin to form stringy networks that trap red blood cells to form clots. Thrombin is a serine protease because it cleaves fibrinogen with its serine residue. Thrombin when made by the body is tethered to blood vessels so that it cannot cause clots throughout the body causing strokes and heart attacks. Additionally, thrombin is only activated for a few seconds to limit the clotted area to the injured area<ref>January 2002 Molecule of the Month by David Goodsell http://www.rcsb.org/pdb/101/motm.do?momID=25 </ref>. However, when fibrin has accumulated at an injury site, sometimes it will break away and occlude a blood vessel which can cause stroke or heart attack. In order to prevent venous thrombosis, blood clots, after surgery or during dialysis when blood is in contact with artificial devices, Heparin is normally administered. Unfortunately Heparin is neutralized by plasma proteins in the blood, is less efficient for the inhibition of clot bound thrombin, and can trigger an enormous immune response. Antithrombotic drugs like Hirudin will be given if Heparin is not able to be tolerated or if the person receives regular dialysis. Hirudin administration require large doses to maintain proper inhibition of Thrombin which heavily taxes the body. Chemists have been working on designer drugs to increase selectivity and potency. One compound which has shown great selectivity and potency in vitro is inhibitor 65.<ref> DOI: 10.1002/cmdc.201200292</ref>
===Phe-Pro-p-amidinobenzylamine===
An early experiment to find a better thrombin inhibitor yielded a structure that was able to bond to the P1 and P2 sites of Thrombin effectively. In 1996 Lilly research laboratories created D-Phe-Pro-p-amidinobenzylamine by making improvements on the previous structure D-Phe-Pro-Agmatine. The new compound they created bonded to thrombin 130x more than it did to trypsin (also a serine protease), and it was highly selective of thrombin over fibrinolytic enzymes which break down fibrin clots. The inhibitor bound with Thrombin at rates 26,000x greater than with plasmin,<ref> http://voices.yahoo.com/what-fibrinolytic-enzymes-6186058.html?cat=68</ref>, 170,000x greater than with t-Pa, and 400,000x greater than with urokinase.
[[Image:1996 inhibitor rates.png|center 300]]

Its selectivity was gained by binding its nitrogens on the benzamidine group by hydrogen bonding to Asp 189, and by fitting its benzamidine benzene into a hydrophobic pocket with Ser 214-Glu 217 and Asp 189-Glu 192 on the other side. The proline residue is in another hydrophobic pocket made up of His 57, Tyr 60A, Leu 99, and Trp 60D. The rest of this structure is unimportant on review of inhibitor 65 because only the amidinobenzylamine which occupies R1 and the proline which occupies the R2 sit are the same residues on inhibitor 65.<ref> M. R. Wiley, N. Y. Chirgadze, D. K. Clawson, T. J. Craft, D. S. GiffordMoore, N. D. Jones, J. L. Olkowski, L. C. Weir, G. F. Smith, Bioorg. Med. Chem. Lett. 1996, 6, 2387. http://www.sciencedirect.com/science/article/pii/0960894X96004428 </ref>

===P3 and P4 of Inhibitor 65===
[[Image:Inhibitor 65.png|center 200]]
Inhibitor 65 additionally has a P4 sulfonyl group with a methoxy group at the end of the residue. It sits in tight VanderWaals structure with the surrounding residues Leu 99, Tyr 60A, Arg 97, Glu 97, and Asn 98.Additionally, the chlorine points to the carbonyl oxygen of Asn 98 and there is a weak Cl-π bond with Trp 215. For the P3 residue, there the backbone of asparagine forms and anti parallel beta sheet with Gly 216. The alkylated asparagine’s NH binds to water which then connects to Glu 192, and the NH of Gly 219 and Gly 216.
</StructureSection>
This is the <scene name='Sean_Swale/Human_Thrombin_Inhibitor/Thrombin_active_site/2'>active site</scene> of thrombin

[[Image:1ppb-transparent.gif|right|500px]]

==References==
{{reflist}}

File:1996 inhibitor rates.png

2012-11-15T21:03:12Z

Sean Swale: M. R. Wiley, N. Y. Chirgadze, D. K. Clawson, T. J. Craft, D. S. GiffordMoore, N. D. Jones, J. L. Olkowski, L. C. Weir, G. F. Smith, Bioorg. Med. Chem. Lett. 1996, 6, 2387. http://www.sciencedirect.com/science/article/pii/0960894X96004428

== Summary ==
M. R. Wiley, N. Y. Chirgadze, D. K. Clawson, T. J. Craft, D. S. GiffordMoore, N. D. Jones, J. L. Olkowski, L. C. Weir, G. F. Smith, Bioorg. Med. Chem. Lett. 1996, 6, 2387. http://www.sciencedirect.com/science/article/pii/0960894X96004428
== Licensing ==
{{subst:Non-commercial from license selector}}

Sean Swale/Human Thrombin Inhibitor

2012-11-15T21:02:23Z

Sean Swale:

<StructureSection load='3utu' size='500' frame='false' align='right' |caption='Human Thrombin' scene=''>
<scene name='Sean_Swale/Human_Thrombin_Inhibitor/Active_site/1'>Total active site</scene>
===Reasons to develop another Thrombin Inhibitor===
Thrombin is a serine protease that cleaves fibrinogen to allow fibrin to form stringy networks that trap red blood cells to form clots. Thrombin is a serine protease because it cleaves fibrinogen with its serine residue. Thrombin when made by the body is tethered to blood vessels so that it cannot cause clots throughout the body causing strokes and heart attacks. Additionally, thrombin is only activated for a few seconds to limit the clotted area to the injured area<ref>January 2002 Molecule of the Month by David Goodsell http://www.rcsb.org/pdb/101/motm.do?momID=25 </ref>. However, when fibrin has accumulated at an injury site, sometimes it will break away and occlude a blood vessel which can cause stroke or heart attack. In order to prevent venous thrombosis, blood clots, after surgery or during dialysis when blood is in contact with artificial devices, Heparin is normally administered. Unfortunately Heparin is neutralized by plasma proteins in the blood, is less efficient for the inhibition of clot bound thrombin, and can trigger an enormous immune response. Antithrombotic drugs like Hirudin will be given if Heparin is not able to be tolerated or if the person receives regular dialysis. Hirudin administration require large doses to maintain proper inhibition of Thrombin which heavily taxes the body. Chemists have been working on designer drugs to increase selectivity and potency. One compound which has shown great selectivity and potency in vitro is inhibitor 65.<ref> DOI: 10.1002/cmdc.201200292</ref>
===Phe-Pro-p-amidinobenzylamine===
An early experiment to find a better thrombin inhibitor yielded a structure that was able to bond to the P1 and P2 sites of Thrombin effectively. In 1996 Lilly research laboratories created D-Phe-Pro-p-amidinobenzylamine by making improvements on the previous structure D-Phe-Pro-Agmatine. The new compound they created bonded to thrombin 130x more than it did to trypsin (also a serine protease), and it was highly selective of thrombin over fibrinolytic enzymes which break down fibrin clots. The inhibitor bound with Thrombin at rates 26,000x greater than with plasmin,<ref> http://voices.yahoo.com/what-fibrinolytic-enzymes-6186058.html?cat=68</ref>, 170,000x greater than with t-Pa, and 400,000x greater than with urokinase.
[[Image:Inhibitor 65.png|center 300]]

Its selectivity was gained by binding its nitrogens on the benzamidine group by hydrogen bonding to Asp 189, and by fitting its benzamidine benzene into a hydrophobic pocket with Ser 214-Glu 217 and Asp 189-Glu 192 on the other side. The proline residue is in another hydrophobic pocket made up of His 57, Tyr 60A, Leu 99, and Trp 60D. The rest of this structure is unimportant on review of inhibitor 65 because only the amidinobenzylamine which occupies R1 and the proline which occupies the R2 sit are the same residues on inhibitor 65.<ref> M. R. Wiley, N. Y. Chirgadze, D. K. Clawson, T. J. Craft, D. S. GiffordMoore, N. D. Jones, J. L. Olkowski, L. C. Weir, G. F. Smith, Bioorg. Med. Chem. Lett. 1996, 6, 2387. http://www.sciencedirect.com/science/article/pii/0960894X96004428 </ref>

===P3 and P4 of Inhibitor 65===
[[Image:Inhibitor 65.png|center 200]]
Inhibitor 65 additionally has a P4 sulfonyl group with a methoxy group at the end of the residue. It sits in tight VanderWaals structure with the surrounding residues Leu 99, Tyr 60A, Arg 97, Glu 97, and Asn 98.Additionally, the chlorine points to the carbonyl oxygen of Asn 98 and there is a weak Cl-π bond with Trp 215. For the P3 residue, there the backbone of asparagine forms and anti parallel beta sheet with Gly 216. The alkylated asparagine’s NH binds to water which then connects to Glu 192, and the NH of Gly 219 and Gly 216.
</StructureSection>
This is the <scene name='Sean_Swale/Human_Thrombin_Inhibitor/Thrombin_active_site/2'>active site</scene> of thrombin

[[Image:1ppb-transparent.gif|right|500px]]

==References==
{{reflist}}

Sean Swale/Human Thrombin Inhibitor

2012-11-15T21:01:20Z

Sean Swale:

<StructureSection load='3utu' size='500' frame='false' align='right' |caption='Human Thrombin' scene=''>
<scene name='Sean_Swale/Human_Thrombin_Inhibitor/Active_site/1'>Total active site</scene>
===Reasons to develop another Thrombin Inhibitor===
Thrombin is a serine protease that cleaves fibrinogen to allow fibrin to form stringy networks that trap red blood cells to form clots. Thrombin is a serine protease because it cleaves fibrinogen with its serine residue. Thrombin when made by the body is tethered to blood vessels so that it cannot cause clots throughout the body causing strokes and heart attacks. Additionally, thrombin is only activated for a few seconds to limit the clotted area to the injured area<ref>January 2002 Molecule of the Month by David Goodsell http://www.rcsb.org/pdb/101/motm.do?momID=25 </ref>. However, when fibrin has accumulated at an injury site, sometimes it will break away and occlude a blood vessel which can cause stroke or heart attack. In order to prevent venous thrombosis, blood clots, after surgery or during dialysis when blood is in contact with artificial devices, Heparin is normally administered. Unfortunately Heparin is neutralized by plasma proteins in the blood, is less efficient for the inhibition of clot bound thrombin, and can trigger an enormous immune response. Antithrombotic drugs like Hirudin will be given if Heparin is not able to be tolerated or if the person receives regular dialysis. Hirudin administration require large doses to maintain proper inhibition of Thrombin which heavily taxes the body. Chemists have been working on designer drugs to increase selectivity and potency. One compound which has shown great selectivity and potency in vitro is inhibitor 65.<ref> DOI: 10.1002/cmdc.201200292</ref>
===Phe-Pro-p-amidinobenzylamine===
An early experiment to find a better thrombin inhibitor yielded a structure that was able to bond to the P1 and P2 sites of Thrombin effectively. In 1996 Lilly research laboratories created D-Phe-Pro-p-amidinobenzylamine by making improvements on the previous structure D-Phe-Pro-Agmatine. The new compound they created bonded to thrombin 130x more than it did to trypsin (also a serine protease), and it was highly selective of thrombin over fibrinolytic enzymes which break down fibrin clots. The inhibitor bound with Thrombin at rates 26,000x greater than with plasmin,<ref> http://voices.yahoo.com/what-fibrinolytic-enzymes-6186058.html?cat=68</ref>, 170,000x greater than with t-Pa, and 400,000x greater than with urokinase.
[[Image:Inhibitor 65.png|center 300]]
Its selectivity was gained by binding its nitrogens on the benzamidine group by hydrogen bonding to Asp 189, and by fitting its benzamidine benzene into a hydrophobic pocket with Ser 214-Glu 217 and Asp 189-Glu 192 on the other side. The proline residue is in another hydrophobic pocket made up of His 57, Tyr 60A, Leu 99, and Trp 60D. The rest of this structure is unimportant on review of inhibitor 65 because only the amidinobenzylamine which occupies R1 and the proline which occupies the R2 sit are the same residues on inhibitor 65.<ref> M. R. Wiley, N. Y. Chirgadze, D. K. Clawson, T. J. Craft, D. S. GiffordMoore, N. D. Jones, J. L. Olkowski, L. C. Weir, G. F. Smith, Bioorg. Med. Chem. Lett. 1996, 6, 2387. http://www.sciencedirect.com/science/article/pii/0960894X96004428 </ref>

===P3 and P4 of Inhibitor 65===
Inhibitor 65 additionally has a P4 sulfonyl group with a methoxy group at the end of the residue. It sits in tight VanderWaals structure with the surrounding residues Leu 99, Tyr 60A, Arg 97, Glu 97, and Asn 98.Additionally, the chlorine points to the carbonyl oxygen of Asn 98 and there is a weak Cl-π bond with Trp 215. For the P3 residue, there the backbone of asparagine forms and anti parallel beta sheet with Gly 216. The alkylated asparagine’s NH binds to water which then connects to Glu 192, and the NH of Gly 219 and Gly 216.
</StructureSection>
This is the <scene name='Sean_Swale/Human_Thrombin_Inhibitor/Thrombin_active_site/2'>active site</scene> of thrombin

[[Image:1ppb-transparent.gif|right|500px]]

==References==
{{reflist}}

File:Inhibitor 65.png

2012-11-15T20:59:42Z

Sean Swale: Chart Comparing Inhibitors binding affinities http://onlinelibrary.wiley.com/doi/10.1002/cmdc.201200292/abstract;jsessionid=0909B4824847A8F97B0AF851DDF9E201.d04t04

== Summary ==
Chart Comparing Inhibitors binding affinities

http://onlinelibrary.wiley.com/doi/10.1002/cmdc.201200292/abstract;jsessionid=0909B4824847A8F97B0AF851DDF9E201.d04t04
== Licensing ==
{{subst:Non-commercial from license selector}}

Sean Swale/Human Thrombin Inhibitor

2012-11-15T20:54:56Z

Sean Swale:

<StructureSection load='3utu' size='500' frame='false' align='right' |caption='Human Thrombin' scene=''>
<scene name='Sean_Swale/Human_Thrombin_Inhibitor/Active_site/1'>Total active site</scene>
===Reasons to develop another Thrombin Inhibitor===
Thrombin is a serine protease that cleaves fibrinogen to allow fibrin to form stringy networks that trap red blood cells to form clots. Thrombin is a serine protease because it cleaves fibrinogen with its serine residue. Thrombin when made by the body is tethered to blood vessels so that it cannot cause clots throughout the body causing strokes and heart attacks. Additionally, thrombin is only activated for a few seconds to limit the clotted area to the injured area<ref>January 2002 Molecule of the Month by David Goodsell http://www.rcsb.org/pdb/101/motm.do?momID=25 </ref>. However, when fibrin has accumulated at an injury site, sometimes it will break away and occlude a blood vessel which can cause stroke or heart attack. In order to prevent venous thrombosis, blood clots, after surgery or during dialysis when blood is in contact with artificial devices, Heparin is normally administered. Unfortunately Heparin is neutralized by plasma proteins in the blood, is less efficient for the inhibition of clot bound thrombin, and can trigger an enormous immune response. Antithrombotic drugs like Hirudin will be given if Heparin is not able to be tolerated or if the person receives regular dialysis. Hirudin administration require large doses to maintain proper inhibition of Thrombin which heavily taxes the body. Chemists have been working on designer drugs to increase selectivity and potency. One compound which has shown great selectivity and potency in vitro is inhibitor 65.<ref> DOI: 10.1002/cmdc.201200292</ref>
===Phe-Pro-p-amidinobenzylamine===
An early experiment to find a better thrombin inhibitor yielded a structure that was able to bond to the P1 and P2 sites of Thrombin effectively. In 1996 Lilly research laboratories created D-Phe-Pro-p-amidinobenzylamine by making improvements on the previous structure D-Phe-Pro-Agmatine. The new compound they created bonded to thrombin 130x more than it did to trypsin (also a serine protease), and it was highly selective of thrombin over fibrinolytic enzymes which break down fibrin clots. The inhibitor bound with Thrombin at rates 26,000x greater than with plasmin,<ref> http://voices.yahoo.com/what-fibrinolytic-enzymes-6186058.html?cat=68</ref>, 170,000x greater than with t-Pa, and 400,000x greater than with urokinase.

Its selectivity was gained by binding its nitrogens on the benzamidine group by hydrogen bonding to Asp 189, and by fitting its benzamidine benzene into a hydrophobic pocket with Ser 214-Glu 217 and Asp 189-Glu 192 on the other side. The proline residue is in another hydrophobic pocket made up of His 57, Tyr 60A, Leu 99, and Trp 60D. The rest of this structure is unimportant on review of inhibitor 65 because only the amidinobenzylamine which occupies R1 and the proline which occupies the R2 sit are the same residues on inhibitor 65.<ref> M. R. Wiley, N. Y. Chirgadze, D. K. Clawson, T. J. Craft, D. S. GiffordMoore, N. D. Jones, J. L. Olkowski, L. C. Weir, G. F. Smith, Bioorg. Med. Chem. Lett. 1996, 6, 2387. http://www.sciencedirect.com/science/article/pii/0960894X96004428 </ref>

===P3 and P4 of Inhibitor 65===
Inhibitor 65 additionally has a P4 sulfonyl group with a methoxy group at the end of the residue. It sits in tight VanderWaals structure with the surrounding residues Leu 99, Tyr 60A, Arg 97, Glu 97, and Asn 98.Additionally, the chlorine points to the carbonyl oxygen of Asn 98 and there is a weak Cl-π bond with Trp 215. For the P3 residue, there the backbone of asparagine forms and anti parallel beta sheet with Gly 216. The alkylated asparagine’s NH binds to water which then connects to Glu 192, and the NH of Gly 219 and Gly 216.
</StructureSection>
This is the <scene name='Sean_Swale/Human_Thrombin_Inhibitor/Thrombin_active_site/2'>active site</scene> of thrombin

[[Image:1ppb-transparent.gif|right|500px]]

==References==
{{reflist}}

Sean Swale/Human Thrombin Inhibitor

2012-11-15T20:45:58Z

Sean Swale:

<Structure load='3utu' size='500' frame='false' align='right' |caption='Human Thrombin' scene='' StructureSection>
<scene name='Sean_Swale/Human_Thrombin_Inhibitor/Active_site/1'>Total active site</scene>
===Reasons to develop another Thrombin Inhibitor===
Thrombin is a serine protease that cleaves fibrinogen to allow fibrin to form stringy networks that trap red blood cells to form clots. Thrombin is a serine protease because it cleaves fibrinogen with its serine residue. Thrombin when made by the body is tethered to blood vessels so that it cannot cause clots throughout the body causing strokes and heart attacks. Additionally, thrombin is only activated for a few seconds to limit the clotted area to the injured area<ref>January 2002 Molecule of the Month by David Goodsell http://www.rcsb.org/pdb/101/motm.do?momID=25 </ref>. However, when fibrin has accumulated at an injury site, sometimes it will break away and occlude a blood vessel which can cause stroke or heart attack. In order to prevent venous thrombosis, blood clots, after surgery or during dialysis when blood is in contact with artificial devices, Heparin is normally administered. Unfortunately Heparin is neutralized by plasma proteins in the blood, is less efficient for the inhibition of clot bound thrombin, and can trigger an enormous immune response. Antithrombotic drugs like Hirudin will be given if Heparin is not able to be tolerated or if the person receives regular dialysis. Hirudin administration require large doses to maintain proper inhibition of Thrombin which heavily taxes the body. Chemists have been working on designer drugs to increase selectivity and potency. One compound which has shown great selectivity and potency in vitro is inhibitor 65.<ref> DOI: 10.1002/cmdc.201200292</ref>
===Phe-Pro-p-amidinobenzylamine===
An early experiment to find a better thrombin inhibitor yielded a structure that was able to bond to the P1 and P2 sites of Thrombin effectively. In 1996 Lilly research laboratories created D-Phe-Pro-p-amidinobenzylamine by making improvements on the previous structure D-Phe-Pro-Agmatine. The new compound they created bonded to thrombin 130x more than it did to trypsin (also a serine protease), and it was highly selective of thrombin over fibrinolytic enzymes such as 26,000x greater with plasmin<ref> http://voices.yahoo.com/what-fibrinolytic-enzymes-6186058.html?cat=68</ref>, 170,000x greater than t-Pa, and 400,000x greater than urokinase. Its selectivity was gained by binding its nitrogens on the benzamidine group by hydrogen bonding to Asp 189, and by fitting its benzamidine benzene into a hydrophobic pocket with Ser 214-Glu 217 and Asp 189-Glu 192 on the other side. The proline residue is in another hydrophobic pocket made up of His 57, Tyr 60A, Leu 99, and Trp 60D. The rest of this structure is unimportant on review of inhibitor 65 because only the amidinobenzylamine which occupies R1 and the proline which occupies the R2 sit are the same residues on inhibitor 65.<ref> M. R. Wiley, N. Y. Chirgadze, D. K. Clawson, T. J. Craft, D. S. GiffordMoore, N. D. Jones, J. L. Olkowski, L. C. Weir, G. F. Smith, Bioorg. Med. Chem. Lett. 1996, 6, 2387. http://www.sciencedirect.com/science/article/pii/0960894X96004428 </ref>

===P3 and P4 of Inhibitor 65===
Inhibitor 65 additionally has a P4 sulfonyl group with a methoxy group at the end of the residue. It sits in tight VanderWaals structure with the surrounding residues Leu 99, Tyr 60A, Arg 97, Glu 97, and Asn 98.Additionally, the chlorine points to the carbonyl oxygen of Asn 98 and there is a weak Cl-π bond with Trp 215. For the P3 residue, there the backbone of asparagine forms and anti parallel beta sheet with Gly 216. The alkylated asparagine’s NH binds to water which then connects to Glu 192, and the NH of Gly 219 and Gly 216.
</StructureSection>
This is the <scene name='Sean_Swale/Human_Thrombin_Inhibitor/Thrombin_active_site/2'>active site</scene> of thrombin
</StructureSection>
[[Image:1ppb-transparent.gif|right|200px]]

==References==
{{reflist}}

Sean Swale/Human Thrombin Inhibitor

2012-11-15T20:41:24Z

Sean Swale:

[[Image:1ppb-transparent.gif|center|200px]]
<Structure load='3utu' size='500' frame='false' align='right' |caption='Human Thrombin' scene='' StructureSection>
<scene name='Sean_Swale/Human_Thrombin_Inhibitor/Active_site/1'>Total active site</scene>
===Reasons to develop another Thrombin Inhibitor===
Thrombin is a serine protease that cleaves fibrinogen to allow fibrin to form stringy networks that trap red blood cells to form clots. Thrombin is a serine protease because it cleaves fibrinogen with its serine residue. Thrombin when made by the body is tethered to blood vessels so that it cannot cause clots throughout the body causing strokes and heart attacks. Additionally, thrombin is only activated for a few seconds to limit the clotted area to the injured area<ref>January 2002 Molecule of the Month by David Goodsell http://www.rcsb.org/pdb/101/motm.do?momID=25 </ref>. However, when fibrin has accumulated at an injury site, sometimes it will break away and occlude a blood vessel which can cause stroke or heart attack. In order to prevent venous thrombosis, blood clots, after surgery or during dialysis when blood is in contact with artificial devices, Heparin is normally administered. Unfortunately Heparin is neutralized by plasma proteins in the blood, is less efficient for the inhibition of clot bound thrombin, and can trigger an enormous immune response. Antithrombotic drugs like Hirudin will be given if Heparin is not able to be tolerated or if the person receives regular dialysis. Hirudin administration require large doses to maintain proper inhibition of Thrombin which heavily taxes the body. Chemists have been working on designer drugs to increase selectivity and potency. One compound which has shown great selectivity and potency in vitro is inhibitor 65.<ref> DOI: 10.1002/cmdc.201200292</ref>
===Phe-Pro-p-amidinobenzylamine===
An early experiment to find a better thrombin inhibitor yielded a structure that was able to bond to the P1 and P2 sites of Thrombin effectively. In 1996 Lilly research laboratories created D-Phe-Pro-p-amidinobenzylamine by making improvements on the previous structure D-Phe-Pro-Agmatine. The new compound they created bonded to thrombin 130x more than it did to trypsin (also a serine protease), and it was highly selective of thrombin over fibrinolytic enzymes such as 26,000x greater with plasmin<ref> http://voices.yahoo.com/what-fibrinolytic-enzymes-6186058.html?cat=68</ref>, 170,000x greater than t-Pa, and 400,000x greater than urokinase. Its selectivity was gained by binding its nitrogens on the benzamidine group by hydrogen bonding to Asp 189, and by fitting its benzamidine benzene into a hydrophobic pocket with Ser 214-Glu 217 and Asp 189-Glu 192 on the other side. The proline residue is in another hydrophobic pocket made up of His 57, Tyr 60A, Leu 99, and Trp 60D. The rest of this structure is unimportant on review of inhibitor 65 because only the amidinobenzylamine which occupies R1 and the proline which occupies the R2 sit are the same residues on inhibitor 65.<ref> M. R. Wiley, N. Y. Chirgadze, D. K. Clawson, T. J. Craft, D. S. GiffordMoore, N. D. Jones, J. L. Olkowski, L. C. Weir, G. F. Smith, Bioorg. Med. Chem. Lett. 1996, 6, 2387. http://www.sciencedirect.com/science/article/pii/0960894X96004428 </ref>

===P3 and P4 of Inhibitor 65===
Inhibitor 65 additionally has a P4 sulfonyl group with a methoxy group at the end of the residue. It sits in tight VanderWaals structure with the surrounding residues Leu 99, Tyr 60A, Arg 97, Glu 97, and Asn 98.Additionally, the chlorine points to the carbonyl oxygen of Asn 98 and there is a weak Cl-π bond with Trp 215. For the P3 residue, there the backbone of asparagine forms and anti parallel beta sheet with Gly 216. The alkylated asparagine’s NH binds to water which then connects to Glu 192, and the NH of Gly 219 and Gly 216.

This is the <scene name='Sean_Swale/Human_Thrombin_Inhibitor/Thrombin_active_site/2'>active site</scene> of thrombin
</StructureSection>
[[Image:1ppb-transparent.gif|right|200px]]

==References==
{{reflist}}

Sean Swale/Human Thrombin Inhibitor

2012-11-15T20:39:49Z

Sean Swale:

[[Image:1ppb-transparent.gif|center|200px]]
<Structure load='3utu' size='500' frame='false' align='right' |caption='Human Thrombin' scene='Insert optional scene name here' StructureSection>
<scene name='Sean_Swale/Human_Thrombin_Inhibitor/Active_site/1'>Total active site</scene>
===Reasons to develop another Thrombin Inhibitor===
Thrombin is a serine protease that cleaves fibrinogen to allow fibrin to form stringy networks that trap red blood cells to form clots. Thrombin is a serine protease because it cleaves fibrinogen with its serine residue. Thrombin when made by the body is tethered to blood vessels so that it cannot cause clots throughout the body causing strokes and heart attacks. Additionally, thrombin is only activated for a few seconds to limit the clotted area to the injured area<ref>January 2002 Molecule of the Month by David Goodsell http://www.rcsb.org/pdb/101/motm.do?momID=25 </ref>. However, when fibrin has accumulated at an injury site, sometimes it will break away and occlude a blood vessel which can cause stroke or heart attack. In order to prevent venous thrombosis, blood clots, after surgery or during dialysis when blood is in contact with artificial devices, Heparin is normally administered. Unfortunately Heparin is neutralized by plasma proteins in the blood, is less efficient for the inhibition of clot bound thrombin, and can trigger an enormous immune response. Antithrombotic drugs like Hirudin will be given if Heparin is not able to be tolerated or if the person receives regular dialysis. Hirudin administration require large doses to maintain proper inhibition of Thrombin which heavily taxes the body. Chemists have been working on designer drugs to increase selectivity and potency. One compound which has shown great selectivity and potency in vitro is inhibitor 65.<ref> DOI: 10.1002/cmdc.201200292</ref>
===Phe-Pro-p-amidinobenzylamine===
An early experiment to find a better thrombin inhibitor yielded a structure that was able to bond to the P1 and P2 sites of Thrombin effectively. In 1996 Lilly research laboratories created D-Phe-Pro-p-amidinobenzylamine by making improvements on the previous structure D-Phe-Pro-Agmatine. The new compound they created bonded to thrombin 130x more than it did to trypsin (also a serine protease), and it was highly selective of thrombin over fibrinolytic enzymes such as 26,000x greater with plasmin<ref> http://voices.yahoo.com/what-fibrinolytic-enzymes-6186058.html?cat=68</ref>, 170,000x greater than t-Pa, and 400,000x greater than urokinase. Its selectivity was gained by binding its nitrogens on the benzamidine group by hydrogen bonding to Asp 189, and by fitting its benzamidine benzene into a hydrophobic pocket with Ser 214-Glu 217 and Asp 189-Glu 192 on the other side. The proline residue is in another hydrophobic pocket made up of His 57, Tyr 60A, Leu 99, and Trp 60D. The rest of this structure is unimportant on review of inhibitor 65 because only the amidinobenzylamine which occupies R1 and the proline which occupies the R2 sit are the same residues on inhibitor 65.<ref> M. R. Wiley, N. Y. Chirgadze, D. K. Clawson, T. J. Craft, D. S. GiffordMoore, N. D. Jones, J. L. Olkowski, L. C. Weir, G. F. Smith, Bioorg. Med. Chem. Lett. 1996, 6, 2387. http://www.sciencedirect.com/science/article/pii/0960894X96004428 </ref>

===P3 and P4 of Inhibitor 65===
Inhibitor 65 additionally has a P4 sulfonyl group with a methoxy group at the end of the residue. It sits in tight VanderWaals structure with the surrounding residues Leu 99, Tyr 60A, Arg 97, Glu 97, and Asn 98.Additionally, the chlorine points to the carbonyl oxygen of Asn 98 and there is a weak Cl-π bond with Trp 215. For the P3 residue, there the backbone of asparagine forms and anti parallel beta sheet with Gly 216. The alkylated asparagine’s NH binds to water which then connects to Glu 192, and the NH of Gly 219 and Gly 216.

This is the <scene name='Sean_Swale/Human_Thrombin_Inhibitor/Thrombin_active_site/2'>active site</scene> of thrombin

==References==
{{reflist}}

Sean Swale/Human Thrombin Inhibitor

2012-11-15T20:39:11Z

Sean Swale:

[[Image:1ppb-transparent.gif|right|200px]]
<Structure load='3utu' size='500' frame='false' align='right' |caption='Human Thrombin' scene='Insert optional scene name here' StructureSection>
<scene name='Sean_Swale/Human_Thrombin_Inhibitor/Active_site/1'>Total active site</scene>
===Reasons to develop another Thrombin Inhibitor===
Thrombin is a serine protease that cleaves fibrinogen to allow fibrin to form stringy networks that trap red blood cells to form clots. Thrombin is a serine protease because it cleaves fibrinogen with its serine residue. Thrombin when made by the body is tethered to blood vessels so that it cannot cause clots throughout the body causing strokes and heart attacks. Additionally, thrombin is only activated for a few seconds to limit the clotted area to the injured area<ref>January 2002 Molecule of the Month by David Goodsell http://www.rcsb.org/pdb/101/motm.do?momID=25 </ref>. However, when fibrin has accumulated at an injury site, sometimes it will break away and occlude a blood vessel which can cause stroke or heart attack. In order to prevent venous thrombosis, blood clots, after surgery or during dialysis when blood is in contact with artificial devices, Heparin is normally administered. Unfortunately Heparin is neutralized by plasma proteins in the blood, is less efficient for the inhibition of clot bound thrombin, and can trigger an enormous immune response. Antithrombotic drugs like Hirudin will be given if Heparin is not able to be tolerated or if the person receives regular dialysis. Hirudin administration require large doses to maintain proper inhibition of Thrombin which heavily taxes the body. Chemists have been working on designer drugs to increase selectivity and potency. One compound which has shown great selectivity and potency in vitro is inhibitor 65.<ref> DOI: 10.1002/cmdc.201200292</ref>
===Phe-Pro-p-amidinobenzylamine===
An early experiment to find a better thrombin inhibitor yielded a structure that was able to bond to the P1 and P2 sites of Thrombin effectively. In 1996 Lilly research laboratories created D-Phe-Pro-p-amidinobenzylamine by making improvements on the previous structure D-Phe-Pro-Agmatine. The new compound they created bonded to thrombin 130x more than it did to trypsin (also a serine protease), and it was highly selective of thrombin over fibrinolytic enzymes such as 26,000x greater with plasmin<ref> http://voices.yahoo.com/what-fibrinolytic-enzymes-6186058.html?cat=68</ref>, 170,000x greater than t-Pa, and 400,000x greater than urokinase. Its selectivity was gained by binding its nitrogens on the benzamidine group by hydrogen bonding to Asp 189, and by fitting its benzamidine benzene into a hydrophobic pocket with Ser 214-Glu 217 and Asp 189-Glu 192 on the other side. The proline residue is in another hydrophobic pocket made up of His 57, Tyr 60A, Leu 99, and Trp 60D. The rest of this structure is unimportant on review of inhibitor 65 because only the amidinobenzylamine which occupies R1 and the proline which occupies the R2 sit are the same residues on inhibitor 65.<ref> M. R. Wiley, N. Y. Chirgadze, D. K. Clawson, T. J. Craft, D. S. GiffordMoore, N. D. Jones, J. L. Olkowski, L. C. Weir, G. F. Smith, Bioorg. Med. Chem. Lett. 1996, 6, 2387. http://www.sciencedirect.com/science/article/pii/0960894X96004428 </ref>

===P3 and P4 of Inhibitor 65===
Inhibitor 65 additionally has a P4 sulfonyl group with a methoxy group at the end of the residue. It sits in tight VanderWaals structure with the surrounding residues Leu 99, Tyr 60A, Arg 97, Glu 97, and Asn 98.Additionally, the chlorine points to the carbonyl oxygen of Asn 98 and there is a weak Cl-π bond with Trp 215. For the P3 residue, there the backbone of asparagine forms and anti parallel beta sheet with Gly 216. The alkylated asparagine’s NH binds to water which then connects to Glu 192, and the NH of Gly 219 and Gly 216.

This is the <scene name='Sean_Swale/Human_Thrombin_Inhibitor/Thrombin_active_site/2'>active site</scene> of thrombin

==References==
{{reflist}}

Sean Swale/Human Thrombin Inhibitor

2012-11-15T20:38:46Z

Sean Swale:

[[Image:1ppb-transparent.gif|left|200px]]
<Structure load='3utu' size='500' frame='false' align='right' |caption='Human Thrombin' scene='Insert optional scene name here' StructureSection>
<scene name='Sean_Swale/Human_Thrombin_Inhibitor/Active_site/1'>Total active site</scene>
===Reasons to develop another Thrombin Inhibitor===
Thrombin is a serine protease that cleaves fibrinogen to allow fibrin to form stringy networks that trap red blood cells to form clots. Thrombin is a serine protease because it cleaves fibrinogen with its serine residue. Thrombin when made by the body is tethered to blood vessels so that it cannot cause clots throughout the body causing strokes and heart attacks. Additionally, thrombin is only activated for a few seconds to limit the clotted area to the injured area<ref>January 2002 Molecule of the Month by David Goodsell http://www.rcsb.org/pdb/101/motm.do?momID=25 </ref>. However, when fibrin has accumulated at an injury site, sometimes it will break away and occlude a blood vessel which can cause stroke or heart attack. In order to prevent venous thrombosis, blood clots, after surgery or during dialysis when blood is in contact with artificial devices, Heparin is normally administered. Unfortunately Heparin is neutralized by plasma proteins in the blood, is less efficient for the inhibition of clot bound thrombin, and can trigger an enormous immune response. Antithrombotic drugs like Hirudin will be given if Heparin is not able to be tolerated or if the person receives regular dialysis. Hirudin administration require large doses to maintain proper inhibition of Thrombin which heavily taxes the body. Chemists have been working on designer drugs to increase selectivity and potency. One compound which has shown great selectivity and potency in vitro is inhibitor 65.<ref> DOI: 10.1002/cmdc.201200292</ref>
===Phe-Pro-p-amidinobenzylamine===
An early experiment to find a better thrombin inhibitor yielded a structure that was able to bond to the P1 and P2 sites of Thrombin effectively. In 1996 Lilly research laboratories created D-Phe-Pro-p-amidinobenzylamine by making improvements on the previous structure D-Phe-Pro-Agmatine. The new compound they created bonded to thrombin 130x more than it did to trypsin (also a serine protease), and it was highly selective of thrombin over fibrinolytic enzymes such as 26,000x greater with plasmin<ref> http://voices.yahoo.com/what-fibrinolytic-enzymes-6186058.html?cat=68</ref>, 170,000x greater than t-Pa, and 400,000x greater than urokinase. Its selectivity was gained by binding its nitrogens on the benzamidine group by hydrogen bonding to Asp 189, and by fitting its benzamidine benzene into a hydrophobic pocket with Ser 214-Glu 217 and Asp 189-Glu 192 on the other side. The proline residue is in another hydrophobic pocket made up of His 57, Tyr 60A, Leu 99, and Trp 60D. The rest of this structure is unimportant on review of inhibitor 65 because only the amidinobenzylamine which occupies R1 and the proline which occupies the R2 sit are the same residues on inhibitor 65.<ref> M. R. Wiley, N. Y. Chirgadze, D. K. Clawson, T. J. Craft, D. S. GiffordMoore, N. D. Jones, J. L. Olkowski, L. C. Weir, G. F. Smith, Bioorg. Med. Chem. Lett. 1996, 6, 2387. http://www.sciencedirect.com/science/article/pii/0960894X96004428 </ref>

===P3 and P4 of Inhibitor 65===
Inhibitor 65 additionally has a P4 sulfonyl group with a methoxy group at the end of the residue. It sits in tight VanderWaals structure with the surrounding residues Leu 99, Tyr 60A, Arg 97, Glu 97, and Asn 98.Additionally, the chlorine points to the carbonyl oxygen of Asn 98 and there is a weak Cl-π bond with Trp 215. For the P3 residue, there the backbone of asparagine forms and anti parallel beta sheet with Gly 216. The alkylated asparagine’s NH binds to water which then connects to Glu 192, and the NH of Gly 219 and Gly 216.

This is the <scene name='Sean_Swale/Human_Thrombin_Inhibitor/Thrombin_active_site/2'>active site</scene> of thrombin

==References==
{{reflist}}

File:1ppb-transparent.gif

2012-11-15T20:37:47Z

Sean Swale: Thrombin with serine in frame. http://www.rcsb.org/pdb/education_discussion/molecule_of_the_month/images/1ppb-transparent.gif

== Summary ==
Thrombin with serine in frame.
http://www.rcsb.org/pdb/education_discussion/molecule_of_the_month/images/1ppb-transparent.gif

== Licensing ==
{{subst:Non-commercial from license selector}}

Sean Swale/Human Thrombin Inhibitor

2012-11-15T20:32:16Z

Sean Swale:

<Structure load='3utu' size='500' frame='false' align='right' |caption='Human Thrombin' scene='Insert optional scene name here' StructureSection>
<scene name='Sean_Swale/Human_Thrombin_Inhibitor/Active_site/1'>Total active site</scene>
===Reasons to develop another Thrombin Inhibitor===
Thrombin is a serine protease that cleaves fibrinogen to allow fibrin to form stringy networks that trap red blood cells to form clots. Thrombin is a serine protease because it cleaves fibrinogen with its serine residue. Thrombin when made by the body is tethered to blood vessels so that it cannot cause clots throughout the body causing strokes and heart attacks. Additionally, thrombin is only activated for a few seconds to limit the clotted area to the injured area<ref>January 2002 Molecule of the Month by David Goodsell http://www.rcsb.org/pdb/101/motm.do?momID=25 </ref>. However, when fibrin has accumulated at an injury site, sometimes it will break away and occlude a blood vessel which can cause stroke or heart attack. In order to prevent venous thrombosis, blood clots, after surgery or during dialysis when blood is in contact with artificial devices, Heparin is normally administered. Unfortunately Heparin is neutralized by plasma proteins in the blood, is less efficient for the inhibition of clot bound thrombin, and can trigger an enormous immune response. Antithrombotic drugs like Hirudin will be given if Heparin is not able to be tolerated or if the person receives regular dialysis. Hirudin administration require large doses to maintain proper inhibition of Thrombin which heavily taxes the body. Chemists have been working on designer drugs to increase selectivity and potency. One compound which has shown great selectivity and potency in vitro is inhibitor 65.<ref> DOI: 10.1002/cmdc.201200292</ref>
===Phe-Pro-p-amidinobenzylamine===
An early experiment to find a better thrombin inhibitor yielded a structure that was able to bond to the P1 and P2 sites of Thrombin effectively. In 1996 Lilly research laboratories created D-Phe-Pro-p-amidinobenzylamine by making improvements on the previous structure D-Phe-Pro-Agmatine. The new compound they created bonded to thrombin 130x more than it did to trypsin (also a serine protease), and it was highly selective of thrombin over fibrinolytic enzymes such as 26,000x greater with plasmin<ref> http://voices.yahoo.com/what-fibrinolytic-enzymes-6186058.html?cat=68</ref>, 170,000x greater than t-Pa, and 400,000x greater than urokinase. Its selectivity was gained by binding its nitrogens on the benzamidine group by hydrogen bonding to Asp 189, and by fitting its benzamidine benzene into a hydrophobic pocket with Ser 214-Glu 217 and Asp 189-Glu 192 on the other side. The proline residue is in another hydrophobic pocket made up of His 57, Tyr 60A, Leu 99, and Trp 60D. The rest of this structure is unimportant on review of inhibitor 65 because only the amidinobenzylamine which occupies R1 and the proline which occupies the R2 sit are the same residues on inhibitor 65.<ref> M. R. Wiley, N. Y. Chirgadze, D. K. Clawson, T. J. Craft, D. S. GiffordMoore, N. D. Jones, J. L. Olkowski, L. C. Weir, G. F. Smith, Bioorg. Med. Chem. Lett. 1996, 6, 2387. http://www.sciencedirect.com/science/article/pii/0960894X96004428 </ref>

===P3 and P4 of Inhibitor 65===
Inhibitor 65 additionally has a P4 sulfonyl group with a methoxy group at the end of the residue. It sits in tight VanderWaals structure with the surrounding residues Leu 99, Tyr 60A, Arg 97, Glu 97, and Asn 98.Additionally, the chlorine points to the carbonyl oxygen of Asn 98 and there is a weak Cl-π bond with Trp 215. For the P3 residue, there the backbone of asparagine forms and anti parallel beta sheet with Gly 216. The alkylated asparagine’s NH binds to water which then connects to Glu 192, and the NH of Gly 219 and Gly 216.

This is the <scene name='Sean_Swale/Human_Thrombin_Inhibitor/Thrombin_active_site/2'>active site</scene> of thrombin

==References==
{{reflist}}

Sean Swale/Human Thrombin Inhibitor

2012-11-15T18:07:23Z

Sean Swale:

== Human Thrombin Inhibitor ==
Thrombin is a serine protease that cleaves fibrinogen to allow fibrin to form stringy networks that trap red blood cells to form clots. Thrombin is a serine protease because it cleaves fibrinogen with its serine residue. Thrombin when made by the body is tethered to blood vessels so that it cannot cause clots throughout the body causing strokes and heart attacks. Additionally, thrombin is only activated for a few seconds to limit the clotted area to the injured area<ref>January 2002 Molecule of the Month by David Goodsell http://www.rcsb.org/pdb/101/motm.do?momID=25 </ref>. In cases such as dialysis a blood thinner like hirudin is needed to make sure a blood clot is not created in the body. Unfortunately, when hirudin was used it could be required up to four times per week which heavily taxes the body. Thus new thrombin inhibitors with greater specificity for the thrombin binding site were developed in vitro such as inhibitor 65. <ref> DOI: 10.1002/cmdc.201200292</ref>

==Introduction==

<Structure load='3utu' size='500' frame='false' align='right' |caption='Human Thrombin' scene='Insert optional scene name here' StructureSection>
<scene name='Sean_Swale/Human_Thrombin_Inhibitor/Active_site/1'>Total active site</scene>
===Reasons to develop another Thrombin Inhibitor===
Thrombin is a (structure) with four binding sites.
In order to prevent venous thrombosis (blood clots) after surgery or during dialysis when blood is in contact with artificial devices, Heparin is normally administered. Unfortunately Heparin is neutralized by plasma proteins in the blood, is less efficient for the inhibition of clot bound thrombin, and can trigger an enormous immune response. Antithrombotic drugs like Hirudin will be given if Heparin is not able to be tolerated or if the person receives regular dialysis. (Insert reasons why hirudin sucks) Chemists have been working on designer drugs to increase selectivity and potency.
===Phe-Pro-p-amidinobenzylamine===
An early experiment to find a better thrombin inhibitor yielded a structure that was able to bond to the P1 and P2 sites of Thrombin effectively. In 1996 Lilly research laboratories created D-Phe-Pro-p-amidinobenzylamine by making improvements on the previous structure D-Phe-Pro-Agmatine. The new compound they created bonded to thrombin 130x more than it did to trypsin (also a serine protease), and it was highly selective of thrombin over fibrinolytic enzymes such as 26,000x greater with plasmin<ref> http://voices.yahoo.com/what-fibrinolytic-enzymes-6186058.html?cat=68</ref>, 170,000x greater than t-Pa, and 400,000x greater than urokinase. Its selectivity was gained by binding its nitrogens on the benzamidine group by hydrogen bonding to Asp 189, and by fitting its benzamidine benzene into a hydrophobic pocket with Ser 214-Glu 217 and Asp 189-Glu 192 on the other side. The proline residue is in another hydrophobic pocket made up of His 57, Tyr 60A, Leu 99, and Trp 60D. The rest of this structure is unimportant on review of inhibitor 65 because only the amidinobenzylamine which occupies R1 and the proline which occupies the R2 sit are the same residues on inhibitor 65.<ref> M. R. Wiley, N. Y. Chirgadze, D. K. Clawson, T. J. Craft, D. S. GiffordMoore, N. D. Jones, J. L. Olkowski, L. C. Weir, G. F. Smith, Bioorg. Med. Chem. Lett. 1996, 6, 2387. http://www.sciencedirect.com/science/article/pii/0960894X96004428 </ref>

===P3 and P4 of Inhibitor 65===
Inhibitor 65 additionally has a P4 sulfonyl group with a methoxy group at the end of the residue. It sits in tight VanderWaals structure with the surrounding residues Leu 99, Tyr 60A, Arg 97, Glu 97, and Asn 98.Additionally, the chlorine points to the carbonyl oxygen of Asn 98 and there is a weak Cl-π bond with Trp 215. For the P3 residue, there the backbone of asparagine forms and anti parallel beta sheet with Gly 216. The alkylated asparagine’s NH binds to water which then connects to Glu 192, and the NH of Gly 219 and Gly 216.

This is the <scene name='Sean_Swale/Human_Thrombin_Inhibitor/Thrombin_active_site/2'>active site</scene> of thrombin

==References==
{{reflist}}

Sean Swale/Human Thrombin Inhibitor

2012-11-15T17:57:17Z

Sean Swale:

== Human Thrombin Inhibitor ==
Thrombin is a serine protease that cleaves fibrinogen to allow fibrin to form stringy networks that trap red blood cells to form clots. Thrombin is a serine protease because it cleaves fibrinogen with its serine residue. Thrombin when made by the body is tethered to blood vessels so that it cannot cause clots throughout the body causing strokes and heart attacks. Additionally, thrombin is only activated for a few seconds to limit the clotted area to the injured area<ref>January 2002 Molecule of the Month by David Goodsell http://www.rcsb.org/pdb/101/motm.do?momID=25 </ref>. In cases such as dialysis a blood thinner like hirudin is needed to make sure a blood clot is not created in the body. Unfortunately, when hirudin was used it could be required up to four times per week which heavily taxes the body. Thus new thrombin inhibitors with greater specificity for the thrombin binding site were developed in vitro such as inhibitor 65. <ref> DOI: 10.1002/cmdc.201200292</ref>

==Introduction==

<Structure load='3utu' size='500' frame='false' align='right' |caption='Human Thrombin' scene='Insert optional scene name here' StructureSection>
<scene name='Sean_Swale/Human_Thrombin_Inhibitor/Active_site/1'>Total active site</scene>
===Reasons to develop another Thrombin Inhibitor===
Thrombin is a (structure) with four binding sites.
In order to prevent venous thrombosis (blood clots) after surgery or during dialysis when blood is in contact with artificial devices, Heparin is normally administered. Unfortunately Heparin is neutralized by plasma proteins in the blood, is less efficient for the inhibition of clot bound thrombin, and can trigger an enormous immune response. Antithrombotic drugs like Hirudin will be given if Heparin is not able to be tolerated or if the person receives regular dialysis. (Insert reasons why hirudin sucks) Chemists have been working on designer drugs to increase selectivity and potency.
===Phe-Pro-p-amidinobenzylamine===
An early experiment to find a better thrombin inhibitor yielded a structure that was able to bond to the P1 and P2 sites of Thrombin effectively. In 1996 Lilly research laboratories created D-Phe-Pro-p-amidinobenzylamine by making improvements on the previous structure D-Phe-Pro-Agmatine. The new compound they created bonded to thrombin 130x more than it did to trypsin (also a serine protease), and it was highly selective of thrombin over fibrinolytic enzymes such as 26,000x greater with plasmin, 170,000x greater than t-Pa, and 400,000x greater than urokinase. Its selectivity was gained by binding its nitrogens on the benzamidine group by hydrogen bonding to Asp 189, and by fitting its benzamidine benzene into a hydrophobic pocket with Ser 214-Glu 217 and Asp 189-Glu 192 on the other side. The proline residue is in another hydrophobic pocket made up of His 57, Tyr 60A, Leu 99, and Trp 60D. The rest of this structure is unimportant on review of inhibitor 65 because only the amidinobenzylamine which occupies R1 and the proline which occupies the R2 sit are the same residues on inhibitor 65.
===P3 and P4 of Inhibitor 65===
Inhibitor 65 additionally has a P4 sulfonyl group with a methoxy group at the end of the residue. It sits in tight VanderWaals structure with the surrounding residues Leu 99, Tyr 60A, Arg 97, Glu 97, and Asn 98.Additionally, the chlorine points to the carbonyl oxygen of Asn 98 and there is a weak Cl-π bond with Trp 215. For the P3 residue, there the backbone of asparagine forms and anti parallel beta sheet with Gly 216. The alkylated asparagine’s NH binds to water which then connects to Glu 192, and the NH of Gly 219 and Gly 216.

This is the <scene name='Sean_Swale/Human_Thrombin_Inhibitor/Thrombin_active_site/2'>active site</scene> of thrombin

==Inhibitor 65==
The
(p1, p2) <ref> M. R. Wiley, N. Y. Chirgadze, D. K. Clawson, T. J. Craft, D. S. GiffordMoore, N. D. Jones, J. L. Olkowski, L. C. Weir, G. F. Smith, Bioorg. Med. Chem. Lett. 1996, 6, 2387. http://www.sciencedirect.com/science/article/pii/0960894X96004428 </ref>

==References==
{{reflist}}

Sean Swale/Human Thrombin Inhibitor

2012-11-13T23:50:01Z

Sean Swale: