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PDBsum entry 2pk5
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Hydrolase/hydrolase inhibitor
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PDB id
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2pk5
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References listed in PDB file
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Key reference
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Title
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Compensating enthalpic and entropic changes hinder binding affinity optimization.
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Authors
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V.Lafont,
A.A.Armstrong,
H.Ohtaka,
Y.Kiso,
L.Mario amzel,
E.Freire.
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Ref.
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Chem Biol Drug Des, 2007,
69,
413-422.
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PubMed id
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Abstract
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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.
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