Identification of Selective, Cell Active Inhibitors of Protein Arginine Methyltransferase 5 through Structure-Based Virtual Screening and Biological Assays
文献类型：期刊论文
| 作者 | Ye, Fei1; Zhang, Weiyao1; Ye, Xiaoqing1; Jin, Jia1; Lv, Zhengbing1; Luo, Cheng2
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| 刊名 | JOURNAL OF CHEMICAL INFORMATION AND MODELING
 |
| 出版日期 | 2018-05 |
| 卷号 | 58期号:5页码:1066-1073 |
| ISSN号 | 1549-9596 |
| DOI | 10.1021/acs.jcim.8b00050 |
| 文献子类 | Article |
| 英文摘要 | Protein arginine methyltransferase 5 (PRMT5), a type II PRMT enzyme, is reported as an important therapeutic target in leukemia and lymphoma. In the present study, based on the combination of virtual screening and biochemical validations, we discovered a series of small-molecule inhibitors targeting PRMT5. Among those, DC_Y134 exhibited the most potent activity with IC50 value of 1.7 mu M and displayed good selectivity against other methyltransferases. Further treatment with DC_Y134 inhibited the proliferation of several hematological malignancy cell lines by causing cell cycle arrest and apoptosis. Western blot assays indicated that DC_Y134 reduced the cellular symmetrically dimethylated levels. In addition, we analyzed the binding mode of DC_Y134 through molecular docking, which revealed that DC_Y134 occupies the binding site of substrate arginine and explained the selectivity of this inhibitor. Taken together, compound DC_Y134 could be used to elucidate the biological roles of PRMT5 and serve as a lead compound for treatment of hematologic malignancies. |
| WOS关键词 | DRUG DISCOVERY ; IN-VIVO ; PRMT5 ; METHYLATION ; DOCKING ; COMPLEX ; CANCER ; OPTIMIZATION ; PROLIFERATION ; EXPRESSION |
| 资助项目 | Zhejiang Province Natural Science Foundation[LY18H300008] ; Public Projects of Zhejiang Province[2016C31017] ; Zhejiang Provincial Top Key Discipline of Biology[00000000] ; Science Foundation of Zhejiang Sci-Tech University[13042163-Y] ; Science Foundation of Zhejiang Sci-Tech University[13042159-Y] ; 521 Talent Cultivation Plan of Zhejiang Sci-Tech University[00000000] |
| WOS研究方向 | Pharmacology & Pharmacy ; Chemistry ; Computer Science |
| 语种 | 英语 |
| WOS记录号 | WOS:000433634900015 |
| 出版者 | AMER CHEMICAL SOC |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/279773]  |
| 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 | Ye, Fei; Luo, Cheng |
| 作者单位 | 1.Zhejiang Sci Tech Univ, Coll Life Sci, Hangzhou 310018, Zhejiang, Peoples R China; 2.Chinese Acad Sci, Drug Discovery & Design Ctr, Shanghai Inst Materia Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China |
| 推荐引用方式 GB/T 7714 | Ye, Fei,Zhang, Weiyao,Ye, Xiaoqing,et al. Identification of Selective, Cell Active Inhibitors of Protein Arginine Methyltransferase 5 through Structure-Based Virtual Screening and Biological Assays[J]. JOURNAL OF CHEMICAL INFORMATION AND MODELING,2018,58(5):1066-1073. |
| APA | Ye, Fei,Zhang, Weiyao,Ye, Xiaoqing,Jin, Jia,Lv, Zhengbing,&Luo, Cheng.(2018).Identification of Selective, Cell Active Inhibitors of Protein Arginine Methyltransferase 5 through Structure-Based Virtual Screening and Biological Assays.JOURNAL OF CHEMICAL INFORMATION AND MODELING,58(5),1066-1073. |
| MLA | Ye, Fei,et al."Identification of Selective, Cell Active Inhibitors of Protein Arginine Methyltransferase 5 through Structure-Based Virtual Screening and Biological Assays".JOURNAL OF CHEMICAL INFORMATION AND MODELING 58.5(2018):1066-1073. |
入库方式： OAI收割
来源：上海药物研究所
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