Computational investigation on inhibition mechanism of BRAF^V600E by Vemurafenib (PLX4032) and its analogue PLX4720

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• 作者：XiaoYun Wu ; Yu Fu ; YuanYuan Wang ; ShanHe Wan ; JiaJie Zhang
• 关键词：Molecular dynamics (MD) ; Binding free energy calculation ; BRAFV600E ; PLX4032·PLX4720
• 刊名：Medicinal Chemistry Research
• 出版年：2017
• 出版时间：February 2017
• 年：2017
• 卷：26
• 期：2
• 页码：390-396
• 全文大小：
• 刊物主题：Pharmacology/Toxicology; Biochemistry, general; Cell Biology;
• 出版者：Springer US
• ISSN：1554-8120
• 卷排序：26

文摘

BRAFV600E small-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 BRAFV600E kinase 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 BRAFV600E inhibition. 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 BRAFV600E by PLX4032 and PLX4720 and clues for the design of novel potent BRAFV600E inhibitors.