Accumulated evidences suggest that in vivo biological potency of a ligand is more strongly correlated with the binding/unbinding kinetics than equilibrium thermodynamics of protein-ligand interaction (PLI). However, the existing experimental and computational techniques are largely insufficient and limited in large-scale measurements or accurate predictions of the kinetic properties of PLI. In this paper, elaborate efforts have been made to develop inter-consistent, reasonable, and predictive models of the association rate constant (kon), dissociation rate constant (koff), as well as the equilibrium dissociation constant (KD) of a serious of HIV protease inhibitors with different structural skeletons. The results showed that 9 Volsurf descriptors derived from water (OH2) and hydrophobic (DRY) probes are key molecular determinants for the kinetic and thermodynamic properties of HIV-1 protease inhibitors. To the best of our knowledge, it is the first time that inter-consistent and reasonable models with strong prediction power were established for both the kinetic and thermodynamic properties of the HIV protease inhibitors.
Constructing Inter-consistent, Reasonable, and Predictive Models for Both the Kinetic and Thermodynamic Properties of HIV-1 Protease Inhibitors.