2g1q: Difference between revisions

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[[Image:2g1q.gif|left|200px]]<br />

[[Image:2g1q.gif|left|200px]]<br /><applet load="2g1q" size="350" color="white" frame="true" align="right" spinBox="true"

<applet load="2g1q" size="~~450~~" color="white" frame="true" align="right" spinBox="true"

caption="2g1q, resolution 2.51Å" />

'''crystal structure of KSP in complex with inhibitor 9h'''<br />

==Overview==

Molecular modeling in combination with X-ray crystallographic information, was employed to identify a region of the kinesin spindle protein (KSP), binding site not fully utilized by our first generation inhibitors. We, discovered that by appending a propylamine substituent at the C5 carbon of, a dihydropyrazole core, we could effectively fill this unoccupied region, of space and engage in a hydrogen-bonding interaction with the enzyme, backbone. This change led to a second generation compound with increased, potency, a 400-fold enhancement in aqueous solubility at pH 4, and, improved dog pharmacokinetics relative to the first generation compound.

Molecular modeling in combination with X-ray crystallographic information was employed to identify a region of the kinesin spindle protein (KSP) binding site not fully utilized by our first generation inhibitors. We discovered that by appending a propylamine substituent at the C5 carbon of a dihydropyrazole core, we could effectively fill this unoccupied region of space and engage in a hydrogen-bonding interaction with the enzyme backbone. This change led to a second generation compound with increased potency, a 400-fold enhancement in aqueous solubility at pH 4, and improved dog pharmacokinetics relative to the first generation compound.

==About this Structure==

2G1Q is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with MG, ADP and N9H as [http://en.wikipedia.org/wiki/ligands ligands]. Full crystallographic information is available from [http://~~ispc~~.weizmann.ac.il/oca-bin/ocashort?id=2G1Q OCA].

2G1Q is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with <scene name='pdbligand=MG:'>MG</scene>, <scene name='pdbligand=ADP:'>ADP</scene> and <scene name='pdbligand=N9H:'>N9H</scene> as [http://en.wikipedia.org/wiki/ligands ligands]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2G1Q OCA].

==Reference==

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[[Category: ksp-inhibitor complex]]

''Page seeded by [http://~~ispc~~.weizmann.ac.il/oca OCA ] on ~~Mon Nov 12 22~~:13:~~05 2007~~''

''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 17:27:17 2008''

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@@ Line 1: / Line 1: @@
-[[Image:2g1q.gif|left|200px]]<br />
+[[Image:2g1q.gif|left|200px]]<br /><applet load="2g1q" size="350" color="white" frame="true" align="right" spinBox="true"
-<applet load="2g1q" size="450" color="white" frame="true" align="right" spinBox="true"
 caption="2g1q, resolution 2.51&Aring;" />
 '''crystal structure of KSP in complex with inhibitor 9h'''<br />
 ==Overview==
-Molecular modeling in combination with X-ray crystallographic information, was employed to identify a region of the kinesin spindle protein (KSP), binding site not fully utilized by our first generation inhibitors. We, discovered that by appending a propylamine substituent at the C5 carbon of, a dihydropyrazole core, we could effectively fill this unoccupied region, of space and engage in a hydrogen-bonding interaction with the enzyme, backbone. This change led to a second generation compound with increased, potency, a 400-fold enhancement in aqueous solubility at pH 4, and, improved dog pharmacokinetics relative to the first generation compound.
+Molecular modeling in combination with X-ray crystallographic information was employed to identify a region of the kinesin spindle protein (KSP) binding site not fully utilized by our first generation inhibitors. We discovered that by appending a propylamine substituent at the C5 carbon of a dihydropyrazole core, we could effectively fill this unoccupied region of space and engage in a hydrogen-bonding interaction with the enzyme backbone. This change led to a second generation compound with increased potency, a 400-fold enhancement in aqueous solubility at pH 4, and improved dog pharmacokinetics relative to the first generation compound.
 ==About this Structure==
-G1Q is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with MG, ADP and N9H as [http://en.wikipedia.org/wiki/ligands ligands]. Full crystallographic information is available from [http://ispc.weizmann.ac.il/oca-bin/ocashort?id=2G1Q OCA].
+G1Q is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with <scene name='pdbligand=MG:'>MG</scene>, <scene name='pdbligand=ADP:'>ADP</scene> and <scene name='pdbligand=N9H:'>N9H</scene> as [http://en.wikipedia.org/wiki/ligands ligands]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2G1Q OCA].
 ==Reference==
@@ Line 21: / Line 20: @@
 [[Category: ksp-inhibitor complex]]
-''Page seeded by [http://ispc.weizmann.ac.il/oca OCA ] on Mon Nov 12 22:13:05 2007''
+''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 17:27:17 2008''