Discovery of Novel Inhibitors Targeting the Menin-Mixed Lineage Leukemia Interface Using Pharmacophore- and Docking-Based Virtual Screening
文献类型：期刊论文
| 作者 | Xu, Yuan1,2; Yue, Liyan1,2; Wang, Yulan1,2; Xing, Jin1,2; Chen, Zhifeng4; Shi, Zhe3; Liu, Rongfeng3; Liu, Yu-Chih3; Luo, Xiaomin1 ; Jiang, Hualiang1,4
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| 刊名 | JOURNAL OF CHEMICAL INFORMATION AND MODELING
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| 出版日期 | 2016-09 |
| 卷号 | 56期号:9页码:1847-1855 |
| ISSN号 | 1549-9596 |
| DOI | 10.1021/acs.jcim.6b00185 |
| 文献子类 | Article |
| 英文摘要 | Disrupting the interaction between mixed lineage leukemia (MLL) fusion protein and menin provides a therapeutic approach for MLL-mediated leukemia. Here, we aim to discover novel inhibitors targeting the menin-MLL interface with virtual screening. Both structure-based molecular docking and ligand-based pharmacophore models were established, and the models used for compound screening show a remarkable ability to retrieve known active ligands from decoy molecules. Verified by a fluorescence polarization assay, five hits with novel scaffolds were identified. Among them, DCZ_M123 exhibited potent inhibitory activity with an IC50 of 4.71 +/- 0.12 mu M and a K-D of 14.70 +/- 2.13 mu M, and it can effectively inhibit the human MLL-rearranged leukemia cells MV4;11 and KOPN8 with GI(50) values of 0.84 mu M and 0.54 mu M, respectively. |
| WOS关键词 | MLL-FUSION PROTEINS ; TRANSFORMATION ; LEUKEMOGENESIS ; BLOCK ; GENE |
| 资助项目 | National Key Research & Development Plan[2016YF1201003] ; National Basic Research Program[2015CB910304] ; Hi-Tech Research and Development Program of China[2014AA01A302] ; National Natural Science Foundation of China[21210003] ; National Natural Science Foundation of China[81230076] ; National Natural Science Foundation of China[81430084] ; Strategic Priority Research Program of the Chinese Academy of Sciences[XDA12050201] ; Fund of State Key Laboratory of Toxicology and Medical Countermeasures, Academy of Military Medical Science[TMC201505] |
| WOS研究方向 | Pharmacology & Pharmacy ; Chemistry ; Computer Science |
| 语种 | 英语 |
| WOS记录号 | WOS:000384271400022 |
| 出版者 | AMER CHEMICAL SOC |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/275910]  |
| 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 | Luo, Cheng; Zheng, Mingyue |
| 作者单位 | 1.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Drug Discovery & Design Ctr, 555 Zuchongzhi Rd, Shanghai 201203, Peoples R China; 2.Univ Chinese Acad Sci, 19A Yuquan Rd, Beijing 100049, Peoples R China; 3.Shanghai ChemPartner LifeSci Co Ltd, 5 Bldg,998 Halei Rd, Shanghai 201203, Peoples R China; 4.Shanghai Tech Univ, Sch Life Sci & Technol, Shanghai 200031, Peoples R China |
| 推荐引用方式 GB/T 7714 | Xu, Yuan,Yue, Liyan,Wang, Yulan,et al. Discovery of Novel Inhibitors Targeting the Menin-Mixed Lineage Leukemia Interface Using Pharmacophore- and Docking-Based Virtual Screening[J]. JOURNAL OF CHEMICAL INFORMATION AND MODELING,2016,56(9):1847-1855. |
| APA | Xu, Yuan.,Yue, Liyan.,Wang, Yulan.,Xing, Jin.,Chen, Zhifeng.,...&Zheng, Mingyue.(2016).Discovery of Novel Inhibitors Targeting the Menin-Mixed Lineage Leukemia Interface Using Pharmacophore- and Docking-Based Virtual Screening.JOURNAL OF CHEMICAL INFORMATION AND MODELING,56(9),1847-1855. |
| MLA | Xu, Yuan,et al."Discovery of Novel Inhibitors Targeting the Menin-Mixed Lineage Leukemia Interface Using Pharmacophore- and Docking-Based Virtual Screening".JOURNAL OF CHEMICAL INFORMATION AND MODELING 56.9(2016):1847-1855. |
入库方式： OAI收割
来源：上海药物研究所
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