【作者】 叶艳； 张碧东； 毛瑞风； 罗成； 郑明月； 蒋华良； 陈凯先；

【Author】 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;

【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；

【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DC₁2抑制活性最强,IC₅₀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。更多还原

【Abstract】 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.更多还原