Identification of PRMT5 inhibitors with novel scaffold structures through virtual screening and biological evaluations

被引：4

作者：

Zhang, Qian ^{[1
]}

Zhang, Lun ^{[1
]}

Jin, Jia ^{[1
]}

Fan, Yaohua ^{[2
]}

Wang, Xiaoguang ^{[2
]}

Hu, Haofeng ^{[1
]}

Ye, Xiaoqing ^{[1
,3
]}

Wang, Lei ^{[1
]}

Cao, Chenxi ^{[2
]}

Ye, Fei ^{[1
]}

机构：

[1] Zhejiang Sci Tech Univ, Coll Life Sci & Med, Hangzhou, Peoples R China

[2] Jia Xing Univ, Dept Surg, Affiliated Hosp 2, Jiaxing, Peoples R China

[3] Chinese Acad Sci, Drug Discovery & Design Ctr, Shanghai Inst Materta Med, State Key Lab Drug Res, Shanghai, Peoples R China

来源：

JOURNAL OF MOLECULAR MODELING | 2022年 / 28卷 / 07期

基金：

中国国家自然科学基金;

关键词：

PRMT5; Small-molecule inhibitors; Virtual screening; Molecular docking; Molecular dynamics simulations; ARGININE METHYLTRANSFERASE 5; DISCOVERY; METHYLATION; DOCKING; GENERATION; SOFTWARE; POTENT; MODEL;

D O I：

10.1007/s00894-022-05125-8

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

Protein arginine methyltransferase 5 (PRMT5), an important member in PRMT family, has been validated as a promising anticancer target. In this study, through the combination of virtual screening and biological experiments, we have identified two PRMT5 inhibitors with novel scaffold structures. Among them, compound Y2431 showed moderate activity with IC50 value of 10.09 mu M and displayed good selectivity against other methyltransferases. The molecular docking analysis and molecular dynamics (MD) simulations suggested that the compound occupied the substrate-arginine binding site. Furthermore, Y2431 exhibited anti-proliferative activity to leukemia cells by inducing cell cycle arrest. Overall, the hit compound could provide a novel scaffold for further optimization of small-molecule PRMT5 inhibitors.

引用

页数：9

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