The recognition mechanism of crizotinib on MTH1: influence of chirality on the bioactivity

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ABSTRACTThe mechanism of how (S)-crizotinib or (R)-crizotinib selectively recognises MutT homolog 1 (MTH1) was investigated by molecular dynamics simulations and molecular mechanics/Poisson-Boltzmann surface area (MMPBSA) free energy calculations. Our studies find that (S)-crizotinib could cause much more conformation fluctuation on MTH1 protein than (R)-crizotinib. Compared with (R)-crizotinib, (S)-crizotinib, to a greater degree, inhibited the anti-correlated motion of the whole MTH1 protein, especially the binding site. The closure motion of the binding site was slightly blocked by (R)-crizotinib, which should be attributed to the steric hindrance of (R)-crizotinib on loop 1 and loop 3. The closure motion of the binding site was greatly promoted by (S)-crizotinib, which should be attributed to the hydrogen bond interaction of (S)-crizotinib on loop 1 and loop 3. The stabilised degree of (S)-crizotinib on the binding pocket in MTH1 was more than that of (R)-crizotinib. In the lowest energy point, the presence of (R)-crizotinib made the binding site of MTH1 slightly become smaller, while the presence of (S)-crizotinib made the binding site of MTH1 form a stable hydrogen bond. These supported the experimental finding that the activity of (S)-crizotinib is superior to the (R)-crizotinib activity (IC50 72 vs. 1375 nM). The free energy calculations also confirmed this point. This work could not only illuminate the mechanism of (S)-crizotinib or (R)-crizotinib selectively recognising MTH1, but also provide a guideline of the design of such chiral drugs.