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

BRAF 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 BRAF 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 BRAF. Component analysis of binding free energy revealed that vdWaals interactions play a dominating effect on BRAF 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 BRAF by PLX4032 and PLX4720 and clues for the design of novel potent BRAF inhibitors. [ABSTRACT FROM AUTHOR]