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 Guimin1; Wang Xiang2; Zhu Jianming1; Guo Binbin1; Yang Zhuo1; Xu Zhijian1 ; Li Bo1; Wang Heyao1; Meng Linghua2; Zhu Weiliang1
|
| 刊名 | Acta Pharmacologica Sinica
 |
| 出版日期 | 2017 |
| 卷号 | 38期号:7页码:1057-1068 |
| 关键词 | B-Raf~(V600E) inhibitor anticancer vemurafenib deazapurine fragment reassembly molecular docking structure-activity relationship |
| ISSN号 | 1671-4083 |
| 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 lm is a potent B-Raf~(V600E) inhibitor with an IC_(50) value of 0.05 mumol/L, which was lower than that of vemurafenib (0.13 mumol/L). Moreover, the selectivity of lm against B-Raf~(WT) was enhanced compared with vemurafenib. In addition, lm 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. |
| 资助项目 | supported by the National Natural Science Foundation of China[00000000] ; the National Science and Technology Major Project[00000000] ; the Ministry of Science and Technology[00000000] ; the Natural Science Foundation of Shanghai, China[00000000] ; the State Key Laboratory of Natural and Biomimetic Drugs[00000000] ; the Special Program for Applied Research on Super Computation of the NSFC-Guangdong Joint Fund (the second phase)[00000000] |
| WOS研究方向 | General & Internal Medicine (provided by Clarivate Analytics) |
| 语种 | 英语 |
| CSCD记录号 | CSCD:6012591 |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/269202]  |
| 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 Heyao; Meng Linghua; Zhu Weiliang |
| 作者单位 | 1.Shanghai Institute of Materia Medica, Chinese Academy of Sciences, CAS Key Laboratory of Receptor Research, Shanghai 201203, China.; 2.Shanghai Institute of Materia Medica, Chinese Academy of Sciences, National Key Laboratory of Drug Research, Shanghai 201203, China. |
| 推荐引用方式 GB/T 7714 | Wang Guimin,Wang Xiang,Zhu Jianming,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):1057-1068. |
| APA | Wang Guimin.,Wang Xiang.,Zhu Jianming.,Guo Binbin.,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),1057-1068. |
| MLA | Wang Guimin,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):1057-1068. |
入库方式： OAI收割
来源：上海药物研究所
浏览0
下载0
收藏0
其他版本
除非特别说明，本系统中所有内容都受版权保护，并保留所有权利。