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

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• 作者：Huiyong Sun ; Pengcheng Chen ; Dan Li ; Youyong Li ; Tingjun Hou
• 刊名：Journal of Chemical Theory and Computation
• 出版年：2016
• 出版时间：February 9, 2016
• 年：2016
• 卷：12
• 期：2
• 页码：851-860
• 全文大小：694K
• ISSN：1549-9626

文摘

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.