Enthalpy-entropy compensation in drug-receptor binding

The thermodynamic parameters (Delta G degrees, Delta H degrees, Delta S degrees) of the drug-receptor binding equilibrium derived from equilibrium constant measurements at different temperatures and van't Hoff plots are reviewed. The analysis 186 independent experiments performed on 136 ligands binding to 10 biological receptors and, for comparison, to DNA and to two different enzymes. Delta H degrees and Delta S degrees values correlate according to the regression equation Delta H degrees (kcal mol(-1)) = -9.5 + 278 Delta S degrees (kcal K-1 mol(-1)) with a coefficient of 0.981. The correlating equation is of the form Delta H degrees = beta Delta S degrees and is expected for a case of enthalpy-entropy compensation with a compensation temperature beta = 278 K. The Delta H-Delta S correlation is carefully examined in terms of transmission of the experimental errors and of the representativeness of the experimental sample utilized. The correlation can be considered a true physical constraint for which, in spite of the relatively wide intervals of Delta H degrees and Delta S degrees allowed, the drug-receptor dissociation constant, K-D, can never be smaller than some 10 pM. The physicochemical origin of the Delta H-Delta S compensation is probably related to an intrinsic property of the hydrogen bond, which is the main force determining the association of the participants (drug, receptor binding site, water) in the drug-receptor binding equilibrium.