TY - JOUR
T1 - The application of thermodynamic methods in drug design
AU - Velazquez-Campoy, Adrian
AU - Luque, Irene
AU - Freire, Ernesto
N1 - Funding Information:
Supported by grants from the National Institutes of Health GM 57144 and GM 51362 to E. Freire A. Velazquez-Campoy was partially supported by a postdoctoral fellowship from the Universidad de Granada, Spain (Plan Propio 1999). I. Luque is a recipient of postdoctoral fellowship from the “Fundación Ramón Areces”, Madrid, Spain.
PY - 2001/12/14
Y1 - 2001/12/14
N2 - The optimization of lead compounds as viable drug candidates involves the optimization of their binding affinity towards the selected target. The binding affinity, Ka, is determined by the Gibbs energy of binding, ΔG, which in turn is determined by the enthalpy, ΔH, and entropy, ΔS, changes (ΔG = ΔH - TΔS). In principle, many combinations of ΔH and ΔS values can give rise to the same ΔG 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 constrained ligands. The thermodynamic signature of these ligands is an entropically dominated binding affinity often accompanied by an unfavorable binding enthalpy. Conformationally constrained ligands cannot easily adapt to changes in the geometry of the binding site, being therefore highly susceptible to drug resistance mutations or naturally occurring genetic polymorphisms. The design of ligands with the capability to adapt to a changing target requires the introduction of certain elements of flexibility or the relaxation of some conformational constraints. Since these compounds pay a larger conformational entropy penalty upon binding, the optimization of their binding affinity requires the presence of a favorable binding enthalpy. In this 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 design permits the identification of drug candidates with a lower susceptibility to target mutations causing drug resistance.
AB - The optimization of lead compounds as viable drug candidates involves the optimization of their binding affinity towards the selected target. The binding affinity, Ka, is determined by the Gibbs energy of binding, ΔG, which in turn is determined by the enthalpy, ΔH, and entropy, ΔS, changes (ΔG = ΔH - TΔS). In principle, many combinations of ΔH and ΔS values can give rise to the same ΔG 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 constrained ligands. The thermodynamic signature of these ligands is an entropically dominated binding affinity often accompanied by an unfavorable binding enthalpy. Conformationally constrained ligands cannot easily adapt to changes in the geometry of the binding site, being therefore highly susceptible to drug resistance mutations or naturally occurring genetic polymorphisms. The design of ligands with the capability to adapt to a changing target requires the introduction of certain elements of flexibility or the relaxation of some conformational constraints. Since these compounds pay a larger conformational entropy penalty upon binding, the optimization of their binding affinity requires the presence of a favorable binding enthalpy. In this 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 design permits the identification of drug candidates with a lower susceptibility to target mutations causing drug resistance.
KW - Binding affinity
KW - Drug design
KW - HIV-1 protease
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U2 - 10.1016/S0040-6031(01)00671-2
DO - 10.1016/S0040-6031(01)00671-2
M3 - Article
AN - SCOPUS:0035861396
SN - 0040-6031
VL - 380
SP - 217
EP - 227
JO - Thermochimica Acta
JF - Thermochimica Acta
IS - 2
ER -