Computational investigation on inhibition mechanism of BRAFV600E by Vemurafenib (PLX4032) and its analogue PLX4720
Computational investigation on inhibition mechanism of BRAFV600E by Vemurafenib (PLX4032) and its analogue PLX4720
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DOI：
10.1007/s00044-016-1757-x
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发表时间：
2017-02
影响因子：
2.6
通讯作者：
Xiaoyun Wu;Yu Fu;Yuanyuan Wang;Shanhe Wan;Jiajie Zhang
中科院分区：
文献类型：
--
作者：
Xiaoyun Wu;Yu Fu;Yuanyuan Wang;Shanhe Wan;Jiajie Zhang
近年来，小分子抑制剂作为治疗癌症特别是黑色素瘤的有效药物受到越来越多的关注。在目前的工作中，通过计算研究BRAFV600Ekinase与抑制剂Vemurafenib （PLX4032）及其类似物PLX4720的相互作用细节。基于分子动力学模拟的结合自由能计算表明，配体PLX4032和PLX4720结合并稳定了BRAFV600E的DFG-in构象。结合自由能组分分析表明，vdWaals相互作用对brafv600e抑制起主导作用。此外，每残基结合自由能分解显示，Ile463、Val471、Ala481、Lys483、Leu514、Ile527、Thr529、Gln530、Trp531、Cys532、Phe583、Gly593和Asp594的贡献最大。这些结果与实验数据吻合较好，为了解PLX4032和PLX4720对brafv600e的抑制机制提供了宝贵的资源，并为设计新型有效的brafv600e抑制剂提供了线索。
BRAFV600Esmall-molecule inhibitors have recently received increasing attention as very effective agents for the therapy of cancer, especially melanoma. In this current work, a computational investigation was performed to investigate the interaction details of BRAFV600Ekinase with inhibitors Vemurafenib (PLX4032) and its analog PLX4720. Binding free energy calculations based on molecular dynamics simulations reveal that ligands PLX4032 and PLX4720 bind to and stabilize the DFG-in conformation of BRAFV600E. Component analysis of binding free energy revealed that vdWaals interactions play a dominating effect on BRAFV600Einhibition. Furthermore, the per-residue binding free energy decomposition revealed that the most favorable contribution came from Ile463, Val471, Ala481, Lys483, Leu514, Ile527, Thr529, Gln530, Trp531, Cys532, Phe583, Gly593, and Asp594. These results agree well with experimental data, which provide valuable resources for understanding the inhibition mechanism of BRAFV600Eby PLX4032 and PLX4720 and clues for the design of novel potent BRAFV600Einhibitors.