Discovery of Novel Inhibitors Targeting the Menin-Mixed Lineage Leukemia Interface Using Pharmacophore- and Docking-Based Virtual Screening

doi:10.1021/acs.jcim.6b00185

CORC > 上海药物研究所 > 中国科学院上海药物研究所 > 药物发现与设计中心

	Discovery of Novel Inhibitors Targeting the Menin-Mixed Lineage Leukemia Interface Using Pharmacophore- and Docking-Based Virtual Screening
	Xu, Yuan 1,2; Yue, Liyan 1,2; Wang, Yulan 1,2; Xing, Jin 1,2; Chen, Zhifeng 4; Shi, Zhe 3; Liu, Rongfeng 3; Liu, Yu-Chih 3; Luo, Xiaomin1 ; Jiang, Hualiang1,4
刊名	JOURNAL OF CHEMICAL INFORMATION AND MODELING
	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.
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关键词	MLL-FUSION PROTEINS ; TRANSFORMATION ; LEUKEMOGENESIS ; BLOCK ; GENE
WOS研究方向	Pharmacology & Pharmacy ; Chemistry ; Computer Science
语种	英语
出版者	AMER CHEMICAL SOC
WOS记录号	WOS:000384271400022
内容类型	期刊论文
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.