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Docking-based structural splicing and reassembly strategy to develop novel deazapurine derivatives as potent B-Raf(V600E) inhibitors

文献类型：期刊论文

作者Wang, Gui-min1,2; Wang, Xiang3; Zhu, Jian-ming1; Guo, Bin-bin1,2; Yang, Zhuo1; Xu, Zhi-jian1; Li, Bo1; Wang, He-yao1; Meng, Ling-hua3; Zhu, Wei-liang1
刊名ACTA PHARMACOLOGICA SINICA
出版日期2017-07
卷号38期号:7页码:1059-1068
关键词B-Raf(V600E) inhibitor anticancer vemurafenib deazapurine fragment reassembly molecular docking structure-activity relationship
ISSN号1671-4083
DOI10.1038/aps.2016.173
文献子类Article
英文摘要The mutation of B-Raf(V600E) is widespread in a variety of human cancers. Its inhibitors vemurafenib and dabrafenib have been launched as drugs for treating unresectable melanoma, demonstrating that B-Raf(V600E) is an ideal drug target. This study focused on developing novel B-Raf(V600E) inhibitors as drug leads against various cancers with B-Raf(V600E) mutation. Using molecular modeling approaches, 200 blockbuster drugs were spliced to generate 283 fragments followed by molecular docking to identify potent fragments. Molecular structures of potential inhibitors of B-Raf(V600E) were then obtained by fragment reassembly followed by docking to predict the bioactivity of the reassembled molecules. The structures with high predicted bioactivity were synthesized, followed by in vitro study to identify potent B-Raf(V600E) inhibitors. A highly potent fragment binding to the hinge area of B-Raf(V600E) was identified via a docking-based structural splicing approach. Using the fragment, 14 novel structures were designed by structural reassembly, two of which were predicted to be as strong as marketed B-Raf(V600E) inhibitors. Biological evaluation revealed that compound 1m is a potent B-Raf(V600E) inhibitor with an IC50 value of 0.05 mu mol/L, which was lower than that of vemurafenib (0.13 mu mol/L). Moreover, the selectivity of 1m against B-RafWT was enhanced compared with vemurafenib. In addition, 1m exhibits desirable solubility, bioavailability and metabolic stability in in vitro assays. Thus, a highly potent and selective B-Raf(V600E) inhibitor was designed via a docking-based structural splicing and reassembly strategy and was validated by medicinal synthesis and biological evaluation.
WOS关键词KINASE INHIBITORS ; ACCURATE DOCKING ; RAF INHIBITORS ; DRUG DESIGN ; BRAF ; CANCER ; GLIDE ; MUTATIONS ; DISCOVERY
资助项目National Natural Science Foundation of China[81273435] ; National Natural Science Foundation of China[81302699] ; National Natural Science Foundation of China[81321092] ; National Science and Technology Major Project[2013ZX09103001001] ; Ministry of Science and Technology[2012AA01A305] ; Natural Science Foundation of Shanghai, China[14ZR1447800] ; State Key Laboratory of Natural and Biomimetic Drugs[K20150205] ; Special Program for Applied Research on Super Computation of the NSFC-Guangdong Joint Fund (the second phase)[00000000]
WOS研究方向Chemistry ; Pharmacology & Pharmacy
语种英语
WOS记录号WOS:000404918600009
出版者ACTA PHARMACOLOGICA SINICA
源URL[http://119.78.100.183/handle/2S10ELR8/272587]  
专题药理学第三研究室
药物发现与设计中心
药理学第一研究室
通讯作者Wang, He-yao; Meng, Ling-hua; Zhu, Wei-liang
作者单位1.Chinese Acad Sci, Shanghai Inst Mat Med, CAS Key Lab Receptor Res, Shanghai 201203, Peoples R China;
2.Univ Chinese Acad Sci, Beijing 100049, Peoples R China;
3.Chinese Acad Sci, Shanghai Inst Mat Med, Natl Key Lab Drug Res, Shanghai 201203, Peoples R China
推荐引用方式
GB/T 7714		 Wang, Gui-min,Wang, Xiang,Zhu, Jian-ming,et al. Docking-based structural splicing and reassembly strategy to develop novel deazapurine derivatives as potent B-Raf(V600E) inhibitors[J]. ACTA PHARMACOLOGICA SINICA,2017,38(7):1059-1068.
APA Wang, Gui-min.,Wang, Xiang.,Zhu, Jian-ming.,Guo, Bin-bin.,Yang, Zhuo.,...&Ding, Jian.(2017).Docking-based structural splicing and reassembly strategy to develop novel deazapurine derivatives as potent B-Raf(V600E) inhibitors.ACTA PHARMACOLOGICA SINICA,38(7),1059-1068.
MLA Wang, Gui-min,et al."Docking-based structural splicing and reassembly strategy to develop novel deazapurine derivatives as potent B-Raf(V600E) inhibitors".ACTA PHARMACOLOGICA SINICA 38.7(2017):1059-1068.

入库方式： OAI收割

来源：上海药物研究所

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