Identification of 5-benzylidene-2-phenylthiazolones as potent PRMT5 inhibitors by virtual screening, structural optimization and biological evaluations
文献类型：期刊论文
| 作者 | Zhu, Kongkai2; Tao, Hongrui2,3; Song, Jia-Li2; Jin, Lu1; Zhang, Yuanyuan3; Liu, Jingqiu3; Chen, Zhifeng3; Jiang, Cheng-Shi2; Luo, Cheng3 ; Zhang, Hua2
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| 刊名 | BIOORGANIC CHEMISTRY
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| 出版日期 | 2018-12 |
| 卷号 | 81页码:289-298 |
| 关键词 | PRMT5 inhibitor Arginine methylation Virtual screening Molecular docking Molecular dynamics simulation |
| ISSN号 | 0045-2068 |
| DOI | 10.1016/j.bioorg.2018.08.021 |
| 文献子类 | Article |
| 英文摘要 | Protein arginine methyltransferase 5 (PRMT5) is an epigenetics related enzyme that has been validated as an important therapeutic target for glioblastoma and mantel cell lymphoma. In the present study, 11 novel PRMT5 inhibitors with 5-benzylidene-2-phenylthiazolone scaffold were identified by molecular docking-based virtual screening and structural optimization. Their IC50 values against PRMT5 at enzymatic level were ranging from 0.77 to 23 mu M. As expected, the top two active hits (5 and 19) showed potent anti-proliferative activity against MV4-11 cells with EC50 values lower than 10 mu M and reduced the cellular symmetric arginine dimethylation levels of SmD3 protein. Besides, 5 and 19 demonstrated the mechanism of cell killing in cell cycle arrest and apoptotic effect. The probable binding modes of the two compounds were explored and further verified by molecular dynamics simulation. The structure-activity relationship (SAR) of this class of structures was also discussed and further demonstrated by molecular docking simulation. |
| WOS关键词 | ARGININE METHYLTRANSFERASE 5 ; MOLECULAR-DYNAMICS ; ACCURATE DOCKING ; SM PROTEINS ; CELL-DEATH ; METHYLATION ; COMPLEX ; LYMPHOMA ; HISTONE ; GROWTH |
| 资助项目 | National Natural Science Foundation of China[81803438] ; National Natural Science Foundation of China[21672082] ; National Natural Science Foundation of China[21472208] ; National Natural Science Foundation of China[81625022] ; National Natural Science Foundation of China[81430084] ; Shandong Provincial Natural Science Foundation[ZR2017BH038] ; Shandong Provincial Natural Science Foundation[JQ201721] ; Shandong Key Development Project[2016GSF201209] ; Young Taishan Scholars Program[tsqn20161037] ; Shandong Talents Team Cultivation Plan of University Preponderant Discipline[10027] ; China Postdoctoral Science Foundation[2016M590391] |
| WOS研究方向 | Biochemistry & Molecular Biology ; Chemistry |
| 语种 | 英语 |
| WOS记录号 | WOS:000449428400031 |
| 出版者 | ACADEMIC PRESS INC ELSEVIER SCIENCE |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/279486]  |
| 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 | Jiang, Cheng-Shi; Luo, Cheng; Zhang, Hua |
| 作者单位 | 1.Ulm Univ, Inst Pharmacol Nat Prod & Clin Pharmacol, Ulm, Germany; 2.Univ Jinan, Sch Biol Sci & Technol, Jinan 250022, Shandong, Peoples R China; 3.Chinese Acad Sci, Drug Discovery & Design Ctr, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China |
| 推荐引用方式 GB/T 7714 | Zhu, Kongkai,Tao, Hongrui,Song, Jia-Li,et al. Identification of 5-benzylidene-2-phenylthiazolones as potent PRMT5 inhibitors by virtual screening, structural optimization and biological evaluations[J]. BIOORGANIC CHEMISTRY,2018,81:289-298. |
| APA | Zhu, Kongkai.,Tao, Hongrui.,Song, Jia-Li.,Jin, Lu.,Zhang, Yuanyuan.,...&Zhang, Hua.(2018).Identification of 5-benzylidene-2-phenylthiazolones as potent PRMT5 inhibitors by virtual screening, structural optimization and biological evaluations.BIOORGANIC CHEMISTRY,81,289-298. |
| MLA | Zhu, Kongkai,et al."Identification of 5-benzylidene-2-phenylthiazolones as potent PRMT5 inhibitors by virtual screening, structural optimization and biological evaluations".BIOORGANIC CHEMISTRY 81(2018):289-298. |
入库方式： OAI收割
来源：上海药物研究所
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