Identification of a novel selective small-molecule inhibitor of protein arginine methyltransferase 5 (PRMT5) by virtual screening, resynthesis and biological evaluations
文献类型：期刊论文
| 作者 | Zhu, Kongkai2; Jiang, Chengshi2; Tao, Hongrui2; Liu, Jingqiu1; Zhang, Hua2; Luo, Cheng1
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| 刊名 | BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
 |
| 出版日期 | 2018-05-15 |
| 卷号 | 28期号:9页码:1476-1483 |
| 关键词 | PRMT5 inhibitor Resynthesis Virtual screening Molecular docking Molecular dynamics simulation |
| ISSN号 | 0960-894X |
| DOI | 10.1016/j.bmcl.2018.03.087 |
| 文献子类 | Article |
| 英文摘要 | As one of the most promising anticancer target in protein arginine methyltransferase (PRMT) family, PRMT5 has been drawing more and more attentions, and many efforts have been devoted to develop its inhibitors. In this study, three PRMT5 inhibitors (9, 16, and 23) with novel scaffolds were identified by performing pharmacophore-and docking-based virtual screening combined with in vitro radiometric- based scintillation proximity assay (SPA). Substructure search based on the scaffold of the most active 9 afforded 26 additional analogues, and SPA results indicated that two analogues (9-1 and 9-2) showed increased PRMT5 inhibitory activity compared with the parental compound. Resynthesis of 9, 9-1, and 92 confirmed their PRMT5 enzymatic inhibition activity. In addition, compound 9-1 displayed selectivity against PRMT5 over other key homological members (PRMT1 and CARM1 (PRMT4)). While the structureactivity relationship (SAR) of this series of compounds was discussed to provide clues for further structure optimization, the probable binding modes of active compounds were also probed by molecular docking and molecular dynamics simulations. Finally, the antiproliferative effect of 9-1 on MV4-11 leukemia cell line was confirmed and its impact on regulating the target gene of PRMT5 was also validated. The hit compounds identified in this work have provided more novel scaffolds for future hit-to-lead optimization of small-molecule PRMT5 inhibitors. (C) 2018 Elsevier Ltd. All rights reserved. |
| WOS关键词 | GROWTH-CONTROL ; BREAST-CANCER ; METHYLATION ; EXPRESSION ; PHOSPHORYLATION ; OPTIMIZATION ; ACTIVATION ; CROSSTALK ; E2F-1 |
| 资助项目 | Natural Science Foundation of Shandong Province[ZR2017BH038] ; Natural Science Foundation of Shandong Province[JQ201721] ; Natural Science Foundation of China[21672082] ; Shandong Key Development Project[2016GSF201209] ; Young Taishan Scholars Program[tsqn20161037] ; Shandong Talents Team Cultivation Plan of University Preponderant Discipline[10027] |
| WOS研究方向 | Pharmacology & Pharmacy ; Chemistry |
| 语种 | 英语 |
| WOS记录号 | WOS:000432493900008 |
| 出版者 | PERGAMON-ELSEVIER SCIENCE LTD |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/279758]  |
| 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 |
| 通讯作者 | Zhang, Hua; Luo, Cheng |
| 作者单位 | 1.Chinese Acad Sci, Drug Discovery & Design Ctr, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China 2.Univ Jinan, Sch Biol Sci & Technol, Jinan 250022, Shandong, Peoples R China; |
| 推荐引用方式 GB/T 7714 | Zhu, Kongkai,Jiang, Chengshi,Tao, Hongrui,et al. Identification of a novel selective small-molecule inhibitor of protein arginine methyltransferase 5 (PRMT5) by virtual screening, resynthesis and biological evaluations[J]. BIOORGANIC & MEDICINAL CHEMISTRY LETTERS,2018,28(9):1476-1483. |
| APA | Zhu, Kongkai,Jiang, Chengshi,Tao, Hongrui,Liu, Jingqiu,Zhang, Hua,&Luo, Cheng.(2018).Identification of a novel selective small-molecule inhibitor of protein arginine methyltransferase 5 (PRMT5) by virtual screening, resynthesis and biological evaluations.BIOORGANIC & MEDICINAL CHEMISTRY LETTERS,28(9),1476-1483. |
| MLA | Zhu, Kongkai,et al."Identification of a novel selective small-molecule inhibitor of protein arginine methyltransferase 5 (PRMT5) by virtual screening, resynthesis and biological evaluations".BIOORGANIC & MEDICINAL CHEMISTRY LETTERS 28.9(2018):1476-1483. |
入库方式： OAI收割
来源：上海药物研究所
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