In silico identification of novel kinase inhibitors by targeting B-Rafv660e from natural products database

• Published in: Journal of molecular modeling 2015-04, Vol.21 (4), Article 102
• Main Authors: Wang, Zi-jie, Wan, Zhi-ning, Chen, Xu-dong, Wu, Chuan-fang, Gao, Guo-long, Liu, Rong, Shi, Zheng, Bao, Jin-ku
• Format: Article
• Language: English
• Subjects: Characterization and Evaluation of Materials; Chemistry; Chemistry and Materials Science; Computer Appl. in Life Sciences; Computer Applications in Chemistry; Molecular Medicine; Original Paper; Theoretical and Computational Chemistry
• ISSN: 1610-2940; 0948-5023
• DOI: 10.1007/s00894-015-2647-8

The Ras/Raf/MEK/ERK (MAPK) signaling pathway has gained much attention from scientific community for therapeutic intervention in the past decades, specifically in oncology. Notably, a most prevalent B-Raf v600e mutant in Raf kinase family exhibits elevated kinase activity and results in constitutive activation of the MAPK pathway, thus making it a promising drug target for cancer therapy. Herein, virtual screening is applied to identify its potential inhibitors. Following the 25 ns molecular dynamic (MD) simulations, ZINC38541768, ZINC38541767, and ZINC12496469 are identified as B-Raf v600e potential inhibitors in a DFG-in conformation. Furthermore, according to the molecular mechanics/generalized born surface area (MM/GBSA) method, these three small molecules exhibit similar and good binding affinity toward B-Raf v600e (−38.76 kcal mol −1 , −42.60 kcal mol −1 , and −39.04 kcal mol −1 ). At the same time, several critical residues, such as I463, V471 in the P-loop, and DFG motif residue D594 within the A-loop, are also well clarified. All these results may not only indicate some future applications of inhibitors targeting B-Raf v600e , but also benefit B-Raf v600e harboring cancer patients. Graphical Abstract Novel kinase inhibitors by targeting B-Raf v660e ᅟ