Combining pharmacophore, docking and substructure search approaches to identify and optimize novel B-Raf(V600E) inhibitors

doi:10.1016/j.bmcl.2012.07.039

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	Combining pharmacophore, docking and substructure search approaches to identify and optimize novel B-Raf(V600E) inhibitors
	Xu, Zhijian; Yan, Guirui; Wang, Gaihong; Li, Bo; Zhu, Jianming; Sun, Peng; Zhang, Xiaodong; Luo, Cheng; Wang, Heyao; Zhu, Weiliang
刊名	BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
	2012-09-01
卷号	22 期号:17 页码:5428-5437
关键词	B-Raf(V600E) inhibitors Pharmacophore Docking Substructure search
ISSN号	0960-894X
DOI	10.1016/j.bmcl.2012.07.039
文献子类	Article
英文摘要	In this study for searching novel B-Raf(V600E) inhibitors, pharmacophore-based virtual screening identified 1 as a hit bearing 5-benzylidene-2-thioxodihydropyrimidine-4,6(1H,5H)-dione. Based on 1, scaffold hopping inspired by molecular docking discovered 5-(furan-2-ylmethylene)-2-thioxodihydropyrimidine-4,6(1H,5H)-dione as a new and better scaffold. Substructure search with the new scaffold identified 28 active compounds, among which 12 compounds (42.9%) showed IC50 less than 1 mu M. Especially, compound 3o, which is 10-fold more potent than the hit 1, is a potent inhibitor comparable to that of the marketed drug vemurafenib. (C) 2012 Elsevier Ltd. All rights reserved.
资助项目	Ministry of Science and Technology[2010DFB73280] ; Ministry of Science and Technology[2012CB910403] ; Shanghai Science and Technology Innovation Program[08431900800] ; Natural Science Foundation[20721003] ; Natural Science Foundation[20972174]
WOS关键词	B-RAF ; BRAF ; RESISTANCE ; KINASE ; BRAF(V600E) ; MUTATIONS ; MECHANISM ; DISCOVERY ; MELANOMA ; PLX4032
WOS研究方向	Pharmacology & Pharmacy ; Chemistry
语种	英语
出版者	PERGAMON-ELSEVIER SCIENCE LTD
WOS记录号	WOS:000308046400016
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/277948]
专题	药理学第三研究室药物发现与设计中心
通讯作者	Wang, Heyao
作者单位	Chinese Acad Sci, Shanghai Inst Mat Med, Shanghai 201203, Peoples R China
推荐引用方式 GB/T 7714	Xu, Zhijian,Yan, Guirui,Wang, Gaihong,et al. Combining pharmacophore, docking and substructure search approaches to identify and optimize novel B-Raf(V600E) inhibitors[J]. BIOORGANIC & MEDICINAL CHEMISTRY LETTERS,2012,22(17):5428-5437.
APA	Xu, Zhijian.,Yan, Guirui.,Wang, Gaihong.,Li, Bo.,Zhu, Jianming.,...&Zhu, Weiliang.(2012).Combining pharmacophore, docking and substructure search approaches to identify and optimize novel B-Raf(V600E) inhibitors.BIOORGANIC & MEDICINAL CHEMISTRY LETTERS,22(17),5428-5437.
MLA	Xu, Zhijian,et al."Combining pharmacophore, docking and substructure search approaches to identify and optimize novel B-Raf(V600E) inhibitors".BIOORGANIC & MEDICINAL CHEMISTRY LETTERS 22.17(2012):5428-5437.