Influence of Chirality of Crizotinib on Its MTH1 Protein Inhibitory Activity: Insight from Molecular Dynamics Simulations and Binding Free Energy Calculations.

ABSTRACT: As a promising target for the treatment of lung cancer, the MutT Homolog 1 (MTH1) protein can be inhibited by crizotinib. A recent work shows that the inhibitory potency of (S)-crizotinib against MTH1 is about 20 times over that of (R)-crizotinib. But the detailed molecular mechanism remains unclear. In this study, molecular dynamics (MD) simulations and free energy calculations were used to elucidate the mechanism about the effect of chirality of crizotinib on the inhibitory activity against MTH1. The binding free energy of (S)-crizotinib predicted by the Molecular Mechanics/Generalized Born Surface Area (MM/GBSA) and Adaptive biasing force (ABF) methodologies is much lower than that of (R)-crizotinib, which is consistent with the experimental data. The analysis of the individual energy t

SUBMITTER: Niu Y 

PROVIDER: S-EPMC4683072 | biostudies-literature | 2015

REPOSITORIES: biostudies-literature