HIV-1 Protease Inhibitors:  Enthalpic versus Entropic Optimization of the Binding Affinity

• Published in: Biochemistry (Easton) 2000-03, Vol.39 (9), p.2201-2207
• Main Authors: Velazquez-Campoy, Adrian, Todd, Matthew J, Freire, Ernesto
• Format: Article
• Language: English
• Subjects: AIDS/HIV; Binding Sites - drug effects; Calorimetry, Differential Scanning; Drug Resistance; Entropy; HIV Protease - chemistry; HIV Protease - metabolism; HIV Protease Inhibitors - chemistry; HIV Protease Inhibitors - metabolism; HIV Protease Inhibitors - pharmacology; HIV-1 - enzymology; Human immunodeficiency virus 1; Oligopeptides - chemistry; Oligopeptides - metabolism; Oligopeptides - pharmacology; Protein Binding - drug effects; Protein Conformation - drug effects; Structure-Activity Relationship; Temperature
• ISSN: 0006-2960; 1520-4995
• DOI: 10.1021/bi992399d

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.