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Accumulated evidence suggests that binding kinetic properties—especially dissociation rate constant or drug-target residence time—are crucial factors affecting drug potency. However, quantitative prediction of kinetic properties has always been a challenging task in drug discovery. In this study, the VolSurf method was successfully applied to quantitatively predict the <i>k_off</i> values of the small ligands of heat shock protein 90α (HSP90α), adenosine receptor (AR) and p38 mitogen-activated protein kinase (p38 MAPK). The results showed that few VolSurf descriptors can efficiently capture the key ligand surface properties related to dissociation rate; the resulting models demonstrated to be extremely simple, robust and predictive in comparison with available prediction methods. Therefore, it can be concluded that the VolSurf-based prediction method can be widely applied in the ligand-receptor binding kinetics and de novo drug design researches.