蛋白质精氨酸甲基化转移酶(PRMT5)新型选择性抑制剂的发现研究
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- 英文论文题名：Discovery of Novel selective Inhibitor of Protein Arginine Methyltransferase 5 Using Docking-based Virtual Screening
- 论文作者：叶艳 ; 张碧东 ; 毛瑞风 ; 罗成 ; 郑明月 ; 蒋华良 ; 陈凯先
- 英文论文作者：Yan Ye ; Bidong Zhang ; Ruifeng Mao ; Cheng Luo ; Mingyue Zheng ; Hualiang Jiang ; Kaixian Chen ; Drug Discovery and Design Center ; State Key Laboratory of Drug Research ; Institute of Materia Medica ; Chinese Academy of Sciences ; University of Chinese Academy of Sciences
- 年：2016
- 作者机构：中国科学院上海药物研究所药物发现与设计中心;中国科学院大学;
- 论文关键词：PRMT5 ; 虚拟筛选 ; 表观遗传 ; 药物发现
- 会议召开时间：2016-07-01
- 会议录名称：中国化学会第30届学术年会摘要集-第二十五分会：化学信息学与化学计量学
- 语种：中文
- 分类号：R979.1
- 学会代码：ZGHY
- 会议名称：中国化学会第30届学术年会-第二十五分会 ; 化学信息学与化学计量学
- 会议地点：中国辽宁大连
- 主办单位：中国化学会
- 学会名称：中国化学会
- 页数：1
- 文件大小：228k
- 原文格式：D
- 会议级别：全国
摘要
蛋白质精氨酸甲基转移酶(PRMT5)是一类重要的组蛋白甲基转移酶~1,在一些原发性肿瘤细胞中过表达。抑制PRMT5可能成为治疗癌症的一个重要方法。目前,已报道的针对PRMT5靶标的特异性抑制剂比较少。本研究中我们建立了基于分子对接的虚拟筛选模型,诱饵分子测试表明该模型具有较好区分活性分子的能力。利用该模型我们成功发现了一类活性较好的新型骨架PRMT5抑制剂。其中,化合物DC_12抑制活性最强,IC_(50)值为2.4μM,且对其他甲基化转移酶PRMT1、EZH2、DNMT3A等表现出了明显的选择性,显示了良好的继续开发前景。
Protein arginine methyltransferase-5(PRMT5) is an important type of methyltransferase enzymes,which is overexpressed in primary tumors.Inhibition of PRMT5 can be as a novel therapeutic approach for cancel.There are limited inhibitors in reported studies which are specific to PRMT5.We established molecular docking model and the model performed fairly well at distinguishing actives from inactives.Based on the model,we successfully discovered one type of active compounds with novel skeleton.Among these compound,DC_S12 is the most potent inhibitor with the IC50 value of 2.4μM.The active compound showed high selectivity against other protein methyltransferases,such as PRMT1,EZH2 and DNMT3 A,which shows promise for further development.
Protein arginine methyltransferase-5(PRMT5) is an important type of methyltransferase enzymes,which is overexpressed in primary tumors.Inhibition of PRMT5 can be as a novel therapeutic approach for cancel.There are limited inhibitors in reported studies which are specific to PRMT5.We established molecular docking model and the model performed fairly well at distinguishing actives from inactives.Based on the model,we successfully discovered one type of active compounds with novel skeleton.Among these compound,DC_S12 is the most potent inhibitor with the IC50 value of 2.4μM.The active compound showed high selectivity against other protein methyltransferases,such as PRMT1,EZH2 and DNMT3 A,which shows promise for further development.
引文
[1]Sun,L.;Wang,M.;Lv,Z.;Yang,N.;Liu,Y.;Bao,S.;Gong,W.;Xu,R.M.Proc.Natl.Acad.Sci.2011,108:20538-20543.