Directly Binding Rather than Induced-Fit Dominated Binding Affinity Difference in (S)- and (R)-Crizotinib Bound MTH1

As one of the most successful anticancer drugs, crizotinib is found to be efficient in the suppression of MTH1, a new therapeutic target for RAS-dependent cancers. Deep analysis shows that stereospecificity is prevalent in the binding of crizotinib to MTH1, where the target is more preferred to bind with the (S)-enantiomer of crizotinib. Surprisingly, very similar binding modes were found for the two enantiomers (Huber et al. Nature 2014, 508, 222-227), which puzzled us to ask a question as to why such a subtle structural variation could lead to so large of a binding affinity difference. Thereafter, by using advanced all-atom molecular dynamics simulations, we characterized the free energy surfaces of the binding/unbinding processes of the (S) and (R)-crizotinib enantiomers to/from MTH1. Interestingly, we found that rather than the induced-fit process, which is prevalent in drug selectivity and specificity (Wilson et al. Science 2015, 347, 882-886), the directly binding process has dominated impact on the binding affinity difference of the enantiomers, implying a common mechanism of stereoselectivity of enantiomers.