The application of thermodynamic methods in drug design

Citation
A. Velazquez-campoy et al., The application of thermodynamic methods in drug design, THERMOC ACT, 380(2), 2001, pp. 217-227
Citations number
30
Language
INGLESE
art.tipo
Article
Categorie Soggetti
Spectroscopy /Instrumentation/Analytical Sciences
Journal title
THERMOCHIMICA ACTA
ISSN journal
0040-6031 → ACNP
Volume
380
Issue
2
Year of publication
2001
Pages
217 - 227
Database
ISI
SICI code
0040-6031(200112)380:2<217:TAOTMI>2.0.ZU;2-3
Abstract
The optimization of lead compounds as viable drug candidates involves the o ptimization of their binding affinity towards the selected target. The bind ing affinity, K-a, is determined by the Gibbs energy of binding, DeltaG, wh ich in turn is determined by the enthalpy, DeltaH, and entropy, DeltaS, cha nges (DeltaG = DeltaH - T DeltaS). In principle, many combinations of Delta H and DeltaS values can give rise to the same DeltaG value and, therefore, elicit the same binding affinity. However, enthalpically dominated ligands do not behave the same as entropically dominated ligands. Current paradigms in drug design usually generate highly hydrophobic and conformationally co nstrained ligands. The thermodynamic signature of these ligands is an entro pically dominated binding affinity often accompanied by an unfavorable bind ing enthalpy. Conformationally constrained ligands cannot easily adapt to c hanges in the geometry of the binding site, being therefore highly suscepti ble to drug resistance mutations or naturally occurring genetic polymorphis ms. The design of ligands with the capability to adapt to a changing target requires the introduction of certain elements of flexibility or the relaxa tion of some conformational constraints. Since these compounds pay a larger conformational entropy penalty upon binding, the optimization of their bin ding affinity requires the presence of a favorable binding enthalpy. In thi s paper, experimental and computational strategies aimed at identifying and optimizing enthalpic ligands will be discussed and applied to the case of HIV-1 protease inhibitors. It is shown that a thermodynamic guide to drug d esign permits the identification of drug candidates with a lower susceptibi lity to target mutations causing drug resistance. (C) 2001 Elsevier Science B.V. All rights reserved.