Influence of chirality of crizotinib on Its MTH1 protein inhibitory activity: Insight from molecular dynamics simulations and binding free energy calculations

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 terms suggests that the van der Waals interactions are important for distinguishing the binding of (S)-crizotinib and (R)-crizotinib. The binding free energy decomposition analysis illustrated that residues Tyr7, Phe27, Phe72 and Trp117 were important for the selective binding of (S)-crizotinib to MTH1. The adaptive biasing force (ABF) method was further employed to elucidate the unbinding process of (S)-crizotinib and (R)-crizotinib from the binding pocket of MTH1. ABF simulation results suggest that the reaction coordinates of the (S)-crizotinib from the binding pocket is different from (R)-crizotinib. The results from our study can reveal the details about the effect of chirality on the inhibition activity of crizotinib to MTH1 and provide valuable information for the design of more potent inhibitors.