caa a22 4500 605512442 CHVBK 20210128100655.0 cr unu---uuuuu 210128e20150401xx s 000 0 eng 10.1007/s00894-015-2647-8 doi (NATIONALLICENCE)springer-10.1007/s00894-015-2647-8 In silico identification of novel kinase inhibitors by targeting B-Rafv660e from natural products database [Elektronische Daten] [Zi-jie Wang, Zhi-ning Wan, Xu-dong Chen, Chuan-fang Wu, Guo-long Gao, Rong Liu, Zheng Shi, Jin-ku Bao] 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-Rafv600e 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-Rafv600e 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-Rafv600e (−38.76kcalmol−1, −42.60kcalmol−1, and −39.04kcalmol−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-Rafv600e, but also benefit B-Rafv600e harboring cancer patients. Graphical Abstract Novel kinase inhibitors by targeting B-Rafv660e ᅟ Springer-Verlag Berlin Heidelberg, 2015 B-Rafv600e nationallicence Kinase inhibitors nationallicence MD simulation nationallicence MM/GBSA nationallicence Virtual screening nationallicence Wang Zi-jie School of Life Sciences and Key Laboratory of Bio-resources, Ministry of Education, & State Key Laboratory of Biotherapy, Sichuan University, 610064, Chengdu, China aut Wan Zhi-ning School of Life Sciences and Key Laboratory of Bio-resources, Ministry of Education, & State Key Laboratory of Biotherapy, Sichuan University, 610064, Chengdu, China aut Chen Xu-dong School of Life Sciences and Key Laboratory of Bio-resources, Ministry of Education, & State Key Laboratory of Biotherapy, Sichuan University, 610064, Chengdu, China aut Wu Chuan-fang School of Life Sciences and Key Laboratory of Bio-resources, Ministry of Education, & State Key Laboratory of Biotherapy, Sichuan University, 610064, Chengdu, China aut Gao Guo-long Sichuan International Travel Healthcare Centre, 610041, Chengdu, China aut Liu Rong Medical and Nursing School, Chengdu University, 610015, Chengdou, China aut Shi Zheng Medical and Nursing School, Chengdu University, 610015, Chengdou, China aut Bao Jin-ku School of Life Sciences and Key Laboratory of Bio-resources, Ministry of Education, & State Key Laboratory of Biotherapy, Sichuan University, 610064, Chengdu, China aut Journal of Molecular Modeling Springer Berlin Heidelberg 21/4(2015-04-01), 1-9 1610-2940 21:4<1 2015 21 894 https://doi.org/10.1007/s00894-015-2647-8 text/html Onlinezugriff via DOI BK010053 XK010053 XK010000 Metadata rights reserved Springer special CC-BY-NC licence nationallicence 1 research-article jats NATIONALLICENCE NATIONALLICENCE NL-springer NATIONALLICENCE 856 40 https://doi.org/10.1007/s00894-015-2647-8 text/html Onlinezugriff via DOI NATIONALLICENCE 700 1- Wang Zi-jie School of Life Sciences and Key Laboratory of Bio-resources, Ministry of Education, & State Key Laboratory of Biotherapy, Sichuan University, 610064, Chengdu, China aut NATIONALLICENCE 700 1- Wan Zhi-ning School of Life Sciences and Key Laboratory of Bio-resources, Ministry of Education, & State Key Laboratory of Biotherapy, Sichuan University, 610064, Chengdu, China aut NATIONALLICENCE 700 1- Chen Xu-dong School of Life Sciences and Key Laboratory of Bio-resources, Ministry of Education, & State Key Laboratory of Biotherapy, Sichuan University, 610064, Chengdu, China aut NATIONALLICENCE 700 1- Wu Chuan-fang School of Life Sciences and Key Laboratory of Bio-resources, Ministry of Education, & State Key Laboratory of Biotherapy, Sichuan University, 610064, Chengdu, China aut NATIONALLICENCE 700 1- Gao Guo-long Sichuan International Travel Healthcare Centre, 610041, Chengdu, China aut NATIONALLICENCE 700 1- Liu Rong Medical and Nursing School, Chengdu University, 610015, Chengdou, China aut NATIONALLICENCE 700 1- Shi Zheng Medical and Nursing School, Chengdu University, 610015, Chengdou, China aut NATIONALLICENCE 700 1- Bao Jin-ku School of Life Sciences and Key Laboratory of Bio-resources, Ministry of Education, & State Key Laboratory of Biotherapy, Sichuan University, 610064, Chengdu, China aut NATIONALLICENCE 773 0- Journal of Molecular Modeling Springer Berlin Heidelberg 21/4(2015-04-01), 1-9 1610-2940 21:4<1 2015 21 894