Design of Potent B-RafV600E Inhibitors by MCSS Strategy

Abstract

B-Raf kinase is a vital intermedium in the mitogen-activated protein kinase (MAPK) signaling pathway, which transforms extracellular signals into cellular mechanisms. Mutations in this kinase, for instance, the most common V600E mutation, can lead to the ERK signaling pathologically activated and hence cause severe diseases like somatic tumors. So far, the development of B-Raf inhibitors has made remarkable progress. However, the resistance and relapse of approved Raf drugs have been widely reported, and the optimization for old drugs and the discovery for new inhibitors still remain a significant task.

In this study, we designed and evaluated a series of novel B-Raf^V600E inhibitors. A fragment library has been established before the docking simulation carried out using the MCSS strategy (multi-copy simulation search). The appropriate fragments were reassembled to provide new candidate compounds, which were further screened by iterative docking simulations and molecular dynamics. Bioassays were carried out to evaluate the pharmacological profile of the compounds identified and synthesized. The result showed that compound 5n had an impressive enzyme inhibitory and anti-proliferation activity, suggesting a promising potential in the future study.

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The study shows that our design method and design intent are valid, and we can use the MCSS simulation to carry out the FBDD strategy to design a new inhibitor in other drug design campaigns.

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