title: In silico identification of novel kinase inhibitors by targeting B-Raf(v660e) from natural products database.
abstract: 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.
authors.affiliation: School of Life Sciences and Key Laboratory of Bio-resources, Ministry of Education, & State Key Laboratory of Biotherapy, Sichuan University, Chengdu, 610064, China.
authors.forename: Zi-jie
authors.initials: ZJ
authors.lastname: Wang
authors.forename: Zhi-ning
authors.initials: ZN
authors.lastname: Wan
authors.forename: Xu-dong
authors.initials: XD
authors.lastname: Chen
authors.forename: Chuan-fang
authors.initials: CF
authors.lastname: Wu
authors.forename: Guo-long
authors.initials: GL
authors.lastname: Gao
authors.forename: Rong
authors.initials: R
authors.lastname: Liu
authors.forename: Zheng
authors.initials: Z
authors.lastname: Shi
authors.forename: Jin-ku
authors.initials: JK
authors.lastname: Bao
mesh_terms: D001688:Biological Products / Q000494:pharmacology; D049109:Cell Proliferation / Q000187:drug effects; D006801:Humans; D020929:Mitogen-Activated Protein Kinase Kinases / Q000737:chemistry* / Q000235:genetics; D009154:Mutation; D009369:Neoplasms / Q000188:drug therapy* / Q000235:genetics; D010766:Phosphorylation / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D001688:Biological Products; D047428:Protein Kinase Inhibitors; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D020929:Mitogen-Activated Protein Kinase Kinases
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