Identification of 5-benzylidene-2-phenylthiazolones as potent PRMT5 inhibitors by virtual screening, structural optimization and biological evaluations

doi:10.1016/j.bioorg.2018.08.021

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	Identification of 5-benzylidene-2-phenylthiazolones as potent PRMT5 inhibitors by virtual screening, structural optimization and biological evaluations
	Zhu, Kongkai 2; Tao, Hongrui 2,3; Song, Jia-Li 2; Jin, Lu 1; Zhang, Yuanyuan 3; Liu, Jingqiu 3; Chen, Zhifeng 3; Jiang, Cheng-Shi 2; Luo, Cheng3 ; Zhang, Hua 2
刊名	BIOORGANIC CHEMISTRY
	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.
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关键词	ARGININE METHYLTRANSFERASE 5 ; MOLECULAR-DYNAMICS ; ACCURATE DOCKING ; SM PROTEINS ; CELL-DEATH ; METHYLATION ; COMPLEX ; LYMPHOMA ; HISTONE ; GROWTH
WOS研究方向	Biochemistry & Molecular Biology ; Chemistry
语种	英语
出版者	ACADEMIC PRESS INC ELSEVIER SCIENCE
WOS记录号	WOS:000449428400031
内容类型	期刊论文
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.