Molecular Determinants of the Kinetic Binding Properties of Antihistamines at the Histamine H(1) Receptors

The binding affinity of ligands for their receptors is determined by their kinetic and thermodynamic binding properties. Kinetic analyses of the rate constants of association and dissociation (k(on) and k(off), respectively) of antihistamines have suggested that second-generation antihistamines have a long duration of action owing to the long residence time (1/k(off)) at the H(1) receptors. In this study, we examined the relationship between the kinetic and thermodynamic binding properties of antihistamines, followed by an evaluation of the structural determinants responsible for their kinetic binding properties using quantitative structure–activity relationship (QSAR) analyses. We found that whereas the binding enthalpy and entropy might contribute to the increase and decrease, respectively, in the k(off) values, there was no significant relationship with the k(on) values. QSAR analyses indicated that k(on) and k(off) values could be determined by the descriptors FASA_H (water-accessible surface area of all hydrophobic atoms divided by total water-accessible surface area) and vsurf_CW2 (a 3D molecular field descriptor weighted by capacity factor 2, the ratio of the hydrophilic surface to the total molecular surface), respectively. These findings provide further insight into the mechanisms by which the kinetic binding properties of antihistamines are regulated by their thermodynamic binding forces and physicochemical properties.