中国科学院机构知识库网格
Chinese Academy of Sciences Institutional Repositories Grid
首页 机构 成果 学者
  
  1. CAS IR Grid
  2. 上海药物研究所
  3. 中国科学院上海药物研究所
  4. 国家级研究中心
  5. 原创新药研究全国重点实验室
Discovery of novel selective PRMT5-MTA inhibitors through structure-based virtual screening

文献类型：期刊论文

作者Ma, Ning5,6,7; Chen, Yang5,6,7; Liang, Yiru1,7; Chen, Xiaoxu5,6,7; Song, Fengnan5,6; Su, Zhaoming1,7; Wang, Yajie5,6,7; Zhou, Jingyi3,4,7; Niu, Buying6,7; Hao, Yongxin2,7
刊名BIOORGANIC CHEMISTRY
出版日期2026
卷号168页码:17
关键词PRMT5 inhibitors Structure-based virtual screening MTA selectivity Molecular dynamics simulation SAR analysis
ISSN号0045-2068
DOI10.1016/j.bioorg.2025.109363
英文摘要The PRMT5-MTA complex, which is uniquely present in cancer cells with MTAP gene deletions, represents a compelling target for synthetic lethality strategies in cancer therapy. Despite the identification of PRMT5-MTA inhibitors to date, none have advanced to clinical use, and the chemical diversity among these inhibitors remains limited. Therefore, there is a pressing need for structurally novel inhibitors. Herein, we reported the discovery of new PRMT5-MTA inhibitors identified through structure-based virtual screening. Among these, Compound 14 demonstrated a binding affinity (KD) of 236 nM for the PRMT5-MTA complex, exhibiting 12.0-fold selectivity over the PRMT5-SAM complex as determined by SPR (MTA+ KD = 0.236 mu M, SAM+ KD = 2.84 mu M, ratio = 12.0x) and a stronger inhibitory effect on PRMT5 enzyme activity in the presence of MTA. Molecular dynamics (MD) simulations provided insights into the binding mode of Compound 14 with the PRMT5 protein, facilitating the identification of derivatives 88 and 108, thereby expanding the chemical space of hit compounds. Our findings could not only enhance the chemical diversity of PRMT5-MTA selective inhibitors, but also deepen the understanding of the structure-activity relationship (SAR) governing PRMT5 selectivity. The discovered compounds represent promising starting points for the development and optimization of novel PRMT5-MTA inhibitors.
WOS关键词ARGININE METHYLTRANSFERASE 5 ; PROTEIN ; IDENTIFICATION ; CHEMISTRY ; LIGANDS ; DESIGN ; TARGET ; POTENT ; TOOL
资助项目National Key Research and Development Program of China[2022YFC3400504] ; National Key Research and Development Program of China[2023YFC2305904] ; Strategic Priority Research Program of the Chinese Academy of Sciences[XDB0850000] ; Strategic Priority Research Program of the Chinese Academy of Sciences[XDB0830200] ; Postdoctoral Fellowship Program of CPSF[GZC20232846] ; China Postdoctoral Science Foundation[2024M763419] ; National Natural Science Foundation of China[82404513] ; National Natural Science Foundation of China[T2225002] ; National Natural Science Foundation of China[82273855] ; National Natural Science Foundation of China[82204278] ; SIMM-SHUTCM Traditional Chinese Medicine Innovation Joint Research Program[E2G805H] ; Shanghai Municipal Science and Technology Major Project ; Youth Innovation Promotion Association of CAS[2023296] ; Natural Science Foundation of Shanghai[22ZR1474300] ; Young Elite Scientists Sponsorship Program by CAST[2023QNRC001]
WOS研究方向Biochemistry & Molecular Biology ; Chemistry
语种英语
WOS记录号WOS:001643971600001
出版者ACADEMIC PRESS INC ELSEVIER SCIENCE
源URL[http://119.78.100.183/handle/2S10ELR8/322429]  
专题国家级研究中心_原创新药研究全国重点实验室
通讯作者Zhang, Sulin; Teng, Dan
作者单位1.Nanjing Univ Chinese Med, Sch Chinese Mat Med, Nanjing 210023, Peoples R China
2.Univ Sci & Technol China, Div Life Sci & Med, Hefei 230026, Anhui, Peoples R China
3.Lingang Lab, Shanghai 200031, Peoples R China
4.ShanghaiTech Univ, Sch Phys Sci & Technol, Shanghai 201210, Peoples R China
5.Univ Chinese Acad Sci, Hangzhou Inst Adv Study, Sch Pharmaceut Sci & Technol, Hangzhou 310024, Peoples R China
6.Univ Chinese Acad Sci, Beijing 100049, Peoples R China
7.Chinese Acad Sci, Drug Discovery & Design Ctr, State Key Lab Drug Res, Shanghai Inst Mat Med, Shanghai 201203, Peoples R China
推荐引用方式
GB/T 7714		 Ma, Ning,Chen, Yang,Liang, Yiru,et al. Discovery of novel selective PRMT5-MTA inhibitors through structure-based virtual screening[J]. BIOORGANIC CHEMISTRY,2026,168:17.
APA Ma, Ning.,Chen, Yang.,Liang, Yiru.,Chen, Xiaoxu.,Song, Fengnan.,...&Teng, Dan.(2026).Discovery of novel selective PRMT5-MTA inhibitors through structure-based virtual screening.BIOORGANIC CHEMISTRY,168,17.
MLA Ma, Ning,et al."Discovery of novel selective PRMT5-MTA inhibitors through structure-based virtual screening".BIOORGANIC CHEMISTRY 168(2026):17.

入库方式： OAI收割

来源：上海药物研究所

浏览0
下载0
收藏0
其他版本

除非特别说明，本系统中所有内容都受版权保护，并保留所有权利。