5upj: Difference between revisions

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[[Image:5upj.gif|left|200px]]<br />

[[Image:5upj.gif|left|200px]]<br /><applet load="5upj" size="350" color="white" frame="true" align="right" spinBox="true"

<applet load="5upj" size="~~450~~" color="white" frame="true" align="right" spinBox="true"

caption="5upj, resolution 2.3Å" />

'''HIV-2 PROTEASE/U99283 COMPLEX'''<br />

==Overview==

A unique strategy for the enhancement of secondary binding of an inhibitor, to an enzyme has been demonstrated in the design of new human, immunodeficiency virus (HIV) protease inhibitors. When the planar benzene, ring of a 4-hydroxycoumarin lead compound (1a, Ki = 0.800 microM) was, replaced with medium-sized (i.e., 7-9), conformationally-flexible, alkyl, rings, the enzyme inhibitory activity of the resulting compounds was, dramatically improved, and inhibitors with more than 50-fold better, binding (e.g., 5d, Ki = 0.015 microM) were obtained. X-ray crystal, structures of these inhibitors complexed with HIV protease indicated the, cycloalkyl rings were able to fold into the S1' pocket of the enzyme and, fill it much more effectively than the rigid benzene ring of the, 4-hydroxycoumarin compound. This work has resulted in the identification, of a promising lead structure for the design of potent, deliverable HIV, protease inhibitors. Compound 5d, a small (MW = 324), nonpeptidic, structure, has already shown several advantages over peptidic inhibitors, including high oral bioavailability (91-99%), a relatively long half-life, (4.9 h), and ease of synthesis (three steps).

A unique strategy for the enhancement of secondary binding of an inhibitor to an enzyme has been demonstrated in the design of new human immunodeficiency virus (HIV) protease inhibitors. When the planar benzene ring of a 4-hydroxycoumarin lead compound (1a, Ki = 0.800 microM) was replaced with medium-sized (i.e., 7-9), conformationally-flexible, alkyl rings, the enzyme inhibitory activity of the resulting compounds was dramatically improved, and inhibitors with more than 50-fold better binding (e.g., 5d, Ki = 0.015 microM) were obtained. X-ray crystal structures of these inhibitors complexed with HIV protease indicated the cycloalkyl rings were able to fold into the S1' pocket of the enzyme and fill it much more effectively than the rigid benzene ring of the 4-hydroxycoumarin compound. This work has resulted in the identification of a promising lead structure for the design of potent, deliverable HIV protease inhibitors. Compound 5d, a small (MW = 324), nonpeptidic structure, has already shown several advantages over peptidic inhibitors, including high oral bioavailability (91-99%), a relatively long half-life (4.9 h), and ease of synthesis (three steps).

==About this Structure==

5UPJ is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Human_immunodeficiency_virus_1 Human immunodeficiency virus 1] with UIN as [http://en.wikipedia.org/wiki/ligand ligand]. Active as [http://en.wikipedia.org/wiki/HIV-1_retropepsin HIV-1 retropepsin], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.4.23.16 3.4.23.16] Full crystallographic information is available from [http://~~ispc~~.weizmann.ac.il/oca-bin/ocashort?id=5UPJ OCA].

5UPJ is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Human_immunodeficiency_virus_1 Human immunodeficiency virus 1] with <scene name='pdbligand=UIN:'>UIN</scene> as [http://en.wikipedia.org/wiki/ligand ligand]. Active as [http://en.wikipedia.org/wiki/HIV-1_retropepsin HIV-1 retropepsin], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.4.23.16 3.4.23.16] Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5UPJ OCA].

==Reference==

Line 15:

Line 14:

[[Category: Human immunodeficiency virus 1]]

[[Category: Single protein]]

[[Category: Finzel, B.C.]]

[[Category: Finzel, B C.]]

[[Category: Mulichak, A.M.]]

[[Category: Mulichak, A M.]]

[[Category: Watenpaugh, K.D.]]

[[Category: Watenpaugh, K D.]]

[[Category: UIN]]

[[Category: acid protease]]

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[[Category: protein-substrate interaction ]]

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@@ Line 1: / Line 1: @@
-[[Image:5upj.gif|left|200px]]<br />
+[[Image:5upj.gif|left|200px]]<br /><applet load="5upj" size="350" color="white" frame="true" align="right" spinBox="true"
-<applet load="5upj" size="450" color="white" frame="true" align="right" spinBox="true"
 caption="5upj, resolution 2.3&Aring;" />
 '''HIV-2 PROTEASE/U99283 COMPLEX'''<br />
 ==Overview==
-A unique strategy for the enhancement of secondary binding of an inhibitor, to an enzyme has been demonstrated in the design of new human, immunodeficiency virus (HIV) protease inhibitors. When the planar benzene, ring of a 4-hydroxycoumarin lead compound (1a, Ki = 0.800 microM) was, replaced with medium-sized (i.e., 7-9), conformationally-flexible, alkyl, rings, the enzyme inhibitory activity of the resulting compounds was, dramatically improved, and inhibitors with more than 50-fold better, binding (e.g., 5d, Ki = 0.015 microM) were obtained. X-ray crystal, structures of these inhibitors complexed with HIV protease indicated the, cycloalkyl rings were able to fold into the S1' pocket of the enzyme and, fill it much more effectively than the rigid benzene ring of the, 4-hydroxycoumarin compound. This work has resulted in the identification, of a promising lead structure for the design of potent, deliverable HIV, protease inhibitors. Compound 5d, a small (MW = 324), nonpeptidic, structure, has already shown several advantages over peptidic inhibitors, including high oral bioavailability (91-99%), a relatively long half-life, (4.9 h), and ease of synthesis (three steps).
+A unique strategy for the enhancement of secondary binding of an inhibitor to an enzyme has been demonstrated in the design of new human immunodeficiency virus (HIV) protease inhibitors. When the planar benzene ring of a 4-hydroxycoumarin lead compound (1a, Ki = 0.800 microM) was replaced with medium-sized (i.e., 7-9), conformationally-flexible, alkyl rings, the enzyme inhibitory activity of the resulting compounds was dramatically improved, and inhibitors with more than 50-fold better binding (e.g., 5d, Ki = 0.015 microM) were obtained. X-ray crystal structures of these inhibitors complexed with HIV protease indicated the cycloalkyl rings were able to fold into the S1' pocket of the enzyme and fill it much more effectively than the rigid benzene ring of the 4-hydroxycoumarin compound. This work has resulted in the identification of a promising lead structure for the design of potent, deliverable HIV protease inhibitors. Compound 5d, a small (MW = 324), nonpeptidic structure, has already shown several advantages over peptidic inhibitors, including high oral bioavailability (91-99%), a relatively long half-life (4.9 h), and ease of synthesis (three steps).
 ==About this Structure==
-UPJ is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Human_immunodeficiency_virus_1 Human immunodeficiency virus 1] with UIN as [http://en.wikipedia.org/wiki/ligand ligand]. Active as [http://en.wikipedia.org/wiki/HIV-1_retropepsin HIV-1 retropepsin], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.4.23.16 3.4.23.16] Full crystallographic information is available from [http://ispc.weizmann.ac.il/oca-bin/ocashort?id=5UPJ OCA].
+UPJ is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Human_immunodeficiency_virus_1 Human immunodeficiency virus 1] with <scene name='pdbligand=UIN:'>UIN</scene> as [http://en.wikipedia.org/wiki/ligand ligand]. Active as [http://en.wikipedia.org/wiki/HIV-1_retropepsin HIV-1 retropepsin], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.4.23.16 3.4.23.16] Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5UPJ OCA].
 ==Reference==
@@ Line 15: / Line 14: @@
 [[Category: Human immunodeficiency virus 1]]
 [[Category: Single protein]]
-[[Category: Finzel, B.C.]]
+[[Category: Finzel, B C.]]
-[[Category: Mulichak, A.M.]]
+[[Category: Mulichak, A M.]]
-[[Category: Watenpaugh, K.D.]]
+[[Category: Watenpaugh, K D.]]
 [[Category: UIN]]
 [[Category: acid protease]]
@@ Line 25: / Line 24: @@
 [[Category: protein-substrate interaction ]]
-''Page seeded by [http://ispc.weizmann.ac.il/oca OCA ] on Thu Nov  8 14:59:24 2007''
+''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 19:15:58 2008''