HIV-1 protease inhibitors: Enthalpic versus entropic optimization of the binding affinity

Adrian Velazquez-Campoy, Matthew J. Todd, Ernesto I Freire

Research output: Contribution to journalArticle

Abstract

Existing experimental as well as computational screening methods select potential ligands or drug candidates on the basis of binding affinity. Since the binding affinity is a function of the enthalpy (ΔH) and entropy (ΔS) changes, it is apparent that improved binding can be achieved in different ways: by optimizing ΔH, ΔS, or a combination of both. However, the behavior of enthalpically or entropically optimized inhibitors is fundamentally different, including their response to mutations that may elicit drug resistance. In the design of HIV-1 protease inhibitors, high binding affinity has usually been achieved by preshaping lead compounds to the geometry of the binding site and by incorporating a high degree of hydrophobicity. The thermodynamic consequence of that approach is that the binding affinity of the resulting inhibitors becomes entropically favorable but enthalpically unfavorable. Specifically, the resulting high binding affinity is due to an increased solvation entropy (hydrophobic effect) combined with a reduced loss of conformational entropy of the inhibitor upon binding (structural rigidity). Here we report that tripeptide inhibitors derived from the transframe region of Gag-Pol (Glu-Asp-Leu and Glu-Asp-Phe) bind to the HIV-1 protease with a favorable enthalpy change. This behavior is qualitatively different from that of known inhibitors and points to new strategies for inhibitor design. Since the binding affinities of enthalpically favorable and enthalpically unfavorable inhibitors have opposite temperature dependence, it is possible to design fast screening protocols that simultaneously select inhibitors on the basis of affinity and enthalpy.

Original languageEnglish (US)
Pages (from-to)2201-2207
Number of pages7
JournalBiochemistry®
Volume39
Issue number9
DOIs
StatePublished - Mar 7 2000

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HIV Protease Inhibitors
Entropy
Protease Inhibitors
Enthalpy
Screening
Lead compounds
Solvation
Hydrophobicity
Hydrophobic and Hydrophilic Interactions
Thermodynamics
Drug Resistance
Rigidity
Pharmaceutical Preparations
Binding Sites
Ligands
Mutation
Temperature
Geometry
Human immunodeficiency virus 1 p16 protease

ASJC Scopus subject areas

  • Biochemistry

Cite this

HIV-1 protease inhibitors : Enthalpic versus entropic optimization of the binding affinity. / Velazquez-Campoy, Adrian; Todd, Matthew J.; Freire, Ernesto I.

In: Biochemistry®, Vol. 39, No. 9, 07.03.2000, p. 2201-2207.

Research output: Contribution to journalArticle

Velazquez-Campoy, Adrian ; Todd, Matthew J. ; Freire, Ernesto I. / HIV-1 protease inhibitors : Enthalpic versus entropic optimization of the binding affinity. In: Biochemistry®. 2000 ; Vol. 39, No. 9. pp. 2201-2207.
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