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Constructing Inter-consistent, Reasonable, and Predictive Models for Both the Kinetic and Thermodynamic Properties of HIV-1 Protease Inhibitors.

Constructing Inter-consistent, Reasonable, and Predictive Models for Both the Kinetic and Thermodynamic Properties of HIV-1 Protease Inhibitors.
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Qu S, Huang S, Pan X, Yang L, Mei H,


Qu S, Huang S, Pan X, Yang L, Mei H, (click to view)

Qu S, Huang S, Pan X, Yang L, Mei H,

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Journal of chemical information and modeling 2016 9 14()

Abstract

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.

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