基于结构虚拟筛选发现蛋白质精氨酸甲基转移酶5抑制剂  

Discovery of PRMT5 Inhibitors via Structure-Based Virtual Screening

作　　者：王廷良 张娜娜 翁江[3] 张吉泉 Wang Tingliang;Zhang Nana;Weng Jiang;Zhang Jiquan(College of Pharmacy,Guizhou Medical University,Guiyang,550025;Guizhou Provincial Engineering Technology Research Center for Chemical Drug R&D,Guizhou Medical University,Guiyang,550025;School of Pharmaceutical Sciences,Sun Yat-Sen University,Guangzhou,510006)

机构地区：[1]贵州医科大学药学院 [2]贵州医科大学贵州省化学合成药物研发利用工程技术研究中心,贵阳550025 [3]中山大学药学院,广州510006

出　　处：《化学通报》2023年第9期1137-1145,共9页Chemistry

基　　金：国家自然科学基金项目(22267003,82060625);贵州省自然科学基金项目(黔科合基础-2K[2023]一般305);贵州省优秀青年科技人才计划项目(黔科合平台人才-YQK[2023]030);贵州医科大学优秀青年人才计划项目[(2022)102]资助。

摘　　要：蛋白质精氨酸甲基转移酶5(PRMT5)是蛋白质甲基转移酶家族(PRMTs)的重要一员,其主要生理功能是催化精氨酸单对称二甲基化。PRMT5的上调发生在不同类型的肿瘤中,并与不良预后密切相关,已被视为肿瘤治疗中的潜在靶点。近年来,已有多种PRMT5抑制剂进入临床试验,但目前尚未有药物获批上市。本研究基于Glide对接的虚拟筛选和生物活性实验,发现化合物8018-1271对PRMT5酶的抑制活性IC_(50)值为13.56±0.86μmol/L,并通过分子动力学揭示其与PRMT5蛋白结构域的相互作用模式。本研究所得化合物8018-1271可作为进一步改造的先导化合物,为新型PRMT5抑制剂的发现提供参考。Protein arginine methyltransferases 5(PRMT5)is one of the important members of the protein methyltransferases family(PRMTs),which catalyzes the asymmetric dimethylation of arginine.The up regulation of PRMT5 occurs in different types of tumors and is closely related to their poor prognosis.PRMT5 has been considered as a potential target in tumor therapy.In recent years,many PRMT5 inhibitors have advanced into clinical trials,but no drugs have been approved for marketing.In this work,Glide docking-based virtual screening and subsequent biological evaluation were performed,and the novel PRMT5 inhibitor 8018-1271 was found with an inhibitory ICso value of 13.56±0.86μmol/L.The potential molecular interaction mode of 8018-1271 with PRMT5 protein domain has been investigated by molecular dynamics.Compound 8018-1271 could be used as a lead compound for the development of novel PRMT5 inhibitors.

关 键 词：PRMT5抑制剂 虚拟筛选 分子对接 分子动力学 

分 类 号：TQ460.1[化学工程—制药化工]