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Insights into Resistance Mechanisms of Inhibitors to Mps1 C604Y Mutation via a Comprehensive Molecular Modeling Study

文献类型： 外文期刊

作者： Chen, Yuan 1 ; Yu, Wenquan 2 ; Jiang, Cui-cui 2 ; Zheng, Jin-gui 1 ;

作者机构： 1.Fujian Agr & Forestry Univ, Coll Crop Sci, Fuzhou 350003, Fujian, Peoples R China

2.Fujian Acad Agr Sci, Inst Agr Engn & Technol, Fuzhou 350003, Fujian, Peoples R China

关键词： Mps1; C604Y; molecular modeling; resistance mechanisms

期刊名称：MOLECULES （ 影响因子：4.411； 五年影响因子：4.587 ）

ISSN： 1420-3049

年卷期： 2018 年 23 卷 6 期

页码：

收录情况： SCI

摘要： Mono-polar spindle 1 (Mps1/TTK) represents a protein kinase reported to be vital for cell division processes and is generally regarded as an attractive target for the treatment of hepatocellular carcinoma, breast carcinoma, and colon cancer. However, the C604Y mutation has been linked to acquired resistance. Recently, three potential small-molecule inhibitors of Mps1 (i.e., reversine, NMS-P715, and its derivative Cpd-5) were reported for the C604Y mutation that exhibit significant resistance to NMS-P715 and Cpd-5, but retain affinity for reversine. In this study, classical molecular dynamic (MD) simulations, accelerated MD (aMD) simulations, and umbrella sampling (US) simulations were performed to illustrate the resistance mechanisms of inhibitors to Mps1. The classical MD simulations combined with free energy calculations revealed that reversine features similar binding affinity characteristics to both Mps1(WT) and Mps1(C604Y), but both NMS-P715 and Cpd-5 feature much higher binding affinities to Mps1(WT) than to Mps1(C604Y). The major variations were shown to be controlled by electrostatic energy and the conformational change of A-loop-induced entropy increased. The large conformational changes of Mps1(C604Y) bound to NMS-P715 and Cpd-5 were also observed in aMD simulations. The US simulation results further suggest that reversine and Cpd-5 both exhibit similar dissociation processes from both Mps1(WT) and Mps1(C604Y), but Cpd-5 and NMS-P715 were found to dissociate more easily from Mps1(C604Y) than from Mps1(WT), thus a reduced residence time was responsible for the inhibitors resistance to the C604Y mutation. The physical principles provided by the present study may provide important clues for the discovery and rational design of novel inhibitors to combat the C604Y mutation of Mps1.

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