title: Directly Binding Rather than Induced-Fit Dominated Binding Affinity Difference in (S)- and (R)-Crizotinib Bound MTH1.
abstract: 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.
authors.forename: Huiyong
authors.initials: H
authors.lastname: Sun
authors.forename: Pengcheng
authors.initials: P
authors.lastname: Chen
authors.forename: Dan
authors.initials: D
authors.lastname: Li
authors.affiliation: Institute of Functional Nano & Soft Materials (FUNSOM), Soochow University , Suzhou, Jiangsu 215123, China.
authors.forename: Youyong
authors.initials: Y
authors.lastname: Li
authors.forename: Tingjun
authors.initials: T
authors.lastname: Hou
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry*; D001665:Binding Sites; D000077547:Crizotinib; D045643:DNA Repair Enzymes / Q000737:chemistry* / Q000378:metabolism; D006801:Humans; D056004:Molecular Dynamics Simulation; D010744:Phosphoric Monoester Hydrolases / Q000737:chemistry* / Q000378:metabolism; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D011720:Pyrazoles / Q000737:chemistry*; D011725:Pyridines / Q000737:chemistry*; D013237:Stereoisomerism; D013816:Thermodynamics
chemical_list: D000970:Antineoplastic Agents; D011720:Pyrazoles; D011725:Pyridines; D000077547:Crizotinib; D010744:Phosphoric Monoester Hydrolases; C078207:8-oxodGTPase; D045643:DNA Repair Enzymes