2pk5: Difference between revisions

Revision as of 19:30, 21 February 2008

Crystal Structure of HIV-1 Protease (Q7K, L33I, L63I ) in Complex with KNI-10075

OverviewOverview

A common strategy to improve the potency of drug candidates is to introduce chemical functionalities, like hydrogen bond donors or acceptors, at positions where they are able to establish strong interactions with the target. However, it is often observed that the added functionalities do not necessarily improve potency even if they form strong hydrogen bonds. Here, we explore the thermodynamic and structural basis for those observations. KNI-10033 is a potent experimental HIV-1 protease inhibitor with picomolar affinity against the wild-type enzyme (K(d) = 13 pm). The potency of the inhibitor is the result of favorable enthalpic (DeltaH = -8.2 kcal/mol) and entropic (-TDeltaS = -6.7 kcal/mol) interactions. The replacement of the thioether group in KNI-10033 by a sulfonyl group (KNI-10075) results in a strong hydrogen bond with the amide of Asp 30B of the HIV-1 protease. This additional hydrogen bond improves the binding enthalpy by 3.9 kcal/mol; however, the enthalpy gain is completely compensated by an entropy loss, resulting in no affinity change. Crystallographic and thermodynamic analysis of the inhibitor/protease complexes indicates that the entropy losses are due to a combination of conformational and solvation effects. These results provide a set of practical guidelines aimed at overcoming enthalpy/entropy compensation and improve binding potency.

About this StructureAbout this Structure

2PK5 is a Single protein structure of sequence from Human immunodeficiency virus 1 with and as ligands. Full crystallographic information is available from OCA.

ReferenceReference

Compensating enthalpic and entropic changes hinder binding affinity optimization., Lafont V, Armstrong AA, Ohtaka H, Kiso Y, Mario Amzel L, Freire E, Chem Biol Drug Des. 2007 Jun;69(6):413-22. PMID:17581235

Page seeded by OCA on Thu Feb 21 18:30:21 2008

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@@ Line 4: / Line 4: @@
 ==Overview==
-A common strategy to improve the potency of drug candidates is to, introduce chemical functionalities, like hydrogen bond donors or, acceptors, at positions where they are able to establish strong, interactions with the target. However, it is often observed that the added, functionalities do not necessarily improve potency even if they form, strong hydrogen bonds. Here, we explore the thermodynamic and structural, basis for those observations. KNI-10033 is a potent experimental HIV-1, protease inhibitor with picomolar affinity against the wild-type enzyme, (K(d) = 13 pm). The potency of the inhibitor is the result of favorable, enthalpic (DeltaH = -8.2 kcal/mol) and entropic (-TDeltaS = -6.7 kcal/mol), interactions. The replacement of the thioether group in KNI-10033 by a, sulfonyl group (KNI-10075) results in a strong hydrogen bond with the, amide of Asp 30B of the HIV-1 protease. This additional hydrogen bond, improves the binding enthalpy by 3.9 kcal/mol; however, the enthalpy gain, is completely compensated by an entropy loss, resulting in no affinity, change. Crystallographic and thermodynamic analysis of the, inhibitor/protease complexes indicates that the entropy losses are due to, a combination of conformational and solvation effects. These results, provide a set of practical guidelines aimed at overcoming enthalpy/entropy, compensation and improve binding potency.
+A common strategy to improve the potency of drug candidates is to introduce chemical functionalities, like hydrogen bond donors or acceptors, at positions where they are able to establish strong interactions with the target. However, it is often observed that the added functionalities do not necessarily improve potency even if they form strong hydrogen bonds. Here, we explore the thermodynamic and structural basis for those observations. KNI-10033 is a potent experimental HIV-1 protease inhibitor with picomolar affinity against the wild-type enzyme (K(d) = 13 pm). The potency of the inhibitor is the result of favorable enthalpic (DeltaH = -8.2 kcal/mol) and entropic (-TDeltaS = -6.7 kcal/mol) interactions. The replacement of the thioether group in KNI-10033 by a sulfonyl group (KNI-10075) results in a strong hydrogen bond with the amide of Asp 30B of the HIV-1 protease. This additional hydrogen bond improves the binding enthalpy by 3.9 kcal/mol; however, the enthalpy gain is completely compensated by an entropy loss, resulting in no affinity change. Crystallographic and thermodynamic analysis of the inhibitor/protease complexes indicates that the entropy losses are due to a combination of conformational and solvation effects. These results provide a set of practical guidelines aimed at overcoming enthalpy/entropy compensation and improve binding potency.
 ==About this Structure==
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 [[Category: Human immunodeficiency virus 1]]
 [[Category: Single protein]]
-[[Category: Amzel, L.M.]]
+[[Category: Amzel, L M.]]
-[[Category: Armstrong, A.A.]]
+[[Category: Armstrong, A A.]]
 [[Category: Freire, E.]]
 [[Category: Kiso, Y.]]
@@ Line 22: / Line 22: @@
 [[Category: protease complex]]
-''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Wed Jan 23 14:08:01 2008''
+''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 18:30:21 2008''