2pk5
Crystal Structure of HIV-1 Protease (Q7K, L33I, L63I ) in Complex with KNI-10075
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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 075 and GOL 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
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