Abstract
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 (kon and koff, respectively) of antihistamines have suggested that second-generation antihistamines have a long duration of action owing to the long residence time (1/koff) at the H1 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 koff values, there was no significant relationship with the kon values. QSAR analyses indicated that kon and koff 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.
Highlights
Antihistamines are usually divided into two generations, first and second, with most second-generation antihistamines having fewer side effects such as sedation and hypnosis owing to less penetration into the brain [3,4,5,6]
It has been recently revealed that second-generation antihistamines show a long duration of action owing to a long residence time (1/koff,) at the
◦, i.e., increases in the enthalpy-dependent binding with decreases in the values of tantly with decreases in the values of ∆H°, i.e., increases in the enthalpy-dependent bindforces, not significantly. These results suggested that the ing forces, not significantly (Figure p = 0.058). These results suggested that kinetic and thermodynamic binding parameters might differentially determine the binding the kinetic and thermodynamic binding parameters might differentially determine the affinity for antihistamines, the koff values appeared to be related in part to the binding affinity for antihistamines, the koff values appeared to be related in part thermodynamic binding properties
Summary
The relationship between the kinetic and thermodynamic binding properties of antihistamines is unclear. Reported kinetic binding parameters (kon and koff ) of antihistamines [7,8,9,10,11,12] Wefirst firstexamined examinedthe therelationship relationship between previously determined kinetic bindparameters (k and k and the thermoon off koff) of antihistamines [7,8,9,10,11,12] (Figure 1 and Table 1) and the thering parameters
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