Repositioning organohalogen drugs: a case study for identification of potent B-Raf V600E inhibitors via docking and bioassay

doi:10.1038/srep31074

CORC > 上海药物研究所 > 中国科学院上海药物研究所 > 药物发现与设计中心

	Repositioning organohalogen drugs: a case study for identification of potent B-Raf V600E inhibitors via docking and bioassay
	Li, Yisu 2,3; Guo, Binbin 2; Xu, Zhijian1,2 ; Li, Bo 2; Cai, Tingting 2; Zhang, Xinben 2; Yu, Yuqi 2; Wang, Heyao2 ; Shi, Jiye 4; Zhu, Weiliang2
刊名	Scientific Reports
	2016-08-09
卷号	6
ISSN号	2045-2322
DOI	10.1038/srep31074
文献子类	Article
英文摘要	Drug repositioning has been attracting increasingly attention for its advantages of reducing costs and risks. Statistics showed that around one quarter of the marketed drugs are organohalogens. However, no study has been reported, to the best of our knowledge, to aim at efficiently repositioning organohalogen drugs, which may be attributed to the lack of accurate halogen bonding scoring function. Here, we present a study to show that two organohalogen drugs were successfully repositioned as potent B-Raf V600E inhibitors via molecular docking with halogen bonding scoring function, namely D(3)DOCKxb developed in our lab, and bioassay. After virtual screening by D(3)DOCKxb against the database CMC (Comprehensive Medicinal Chemistry), 3 organohalogen drugs that were predicted to form strong halogen bonding with B-Raf V600E were purchased and tested with ELISA-based assay. In the end, 2 of them, rafoxanide and closantel, were identified as potent inhibitors with IC50 values of 0.07 mu M and 1.90 mu M, respectively, which are comparable to that of vemurafenib (IC50: 0.17 mu M), a marketed drug targeting B-Raf V600E. Single point mutagenesis experiments confirmed the conformations predicted by D(3)DOCKxb. And comparison experiment revealed that halogen bonding scoring function is essential for repositioning those drugs with heavy halogen atoms in their molecular structures.
资助项目	National Major Project[2013ZX09103001-001] ; International Science &Technology Cooperation Program of China[2014DFA31130] ; National Natural Science Foundation of China[81302699] ; National Natural Science Foundation of China[81273435] ; China Postdoctoral Science Foundation[2014T70444] ; State Key Laboratory of Drug Research[SIMM1501KF-07] ; Special Program for Applied Research on Super Computation of the NSFC-Guangdong Joint Fund (the second phase)[00000000]
WOS关键词	PROTEIN-LIGAND INTERACTIONS ; BONDING SCORING FUNCTION ; ACCURATE DOCKING ; DISCOVERY ; DESIGN ; MOLECULES ; GLIDE ; ACTIVATION ; PREDICTION ; PATHWAY
WOS研究方向	Science & Technology - Other Topics
语种	英语
出版者	NATURE PUBLISHING GROUP
WOS记录号	WOS:000381027000001
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/275928]
专题	药物发现与设计中心中科院受体结构与功能重点实验室新药研究国家重点实验室药理学第三研究室
通讯作者	Xu, Zhijian; Wang, Heyao; Zhu, Weiliang
作者单位	1.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China; 2.Chinese Acad Sci, Shanghai Inst Mat Med, Drug Discovery & Design Ctr, CAS Key Lab Receptor Res, Shanghai 201203, Peoples R China; 3.Univ Sci & Technol China, Nano Sci & Technol Inst, Suzhou 215123, Jiangsu, Peoples R China; 4.UCB Biopharma SPRL, Chemin Foriest, Braine Lalleud, Belgium
推荐引用方式 GB/T 7714	Li, Yisu,Guo, Binbin,Xu, Zhijian,et al. Repositioning organohalogen drugs: a case study for identification of potent B-Raf V600E inhibitors via docking and bioassay[J]. Scientific Reports,2016,6.
APA	Li, Yisu.,Guo, Binbin.,Xu, Zhijian.,Li, Bo.,Cai, Tingting.,...&Zhu, Weiliang.(2016).Repositioning organohalogen drugs: a case study for identification of potent B-Raf V600E inhibitors via docking and bioassay.Scientific Reports,6.
MLA	Li, Yisu,et al."Repositioning organohalogen drugs: a case study for identification of potent B-Raf V600E inhibitors via docking and bioassay".Scientific Reports 6(2016).