通过虚拟筛选和生物学评价鉴定新型PRMT5底物竞争性抑制剂  

Identification of Novel Substrate-competitive Inhibitors for PRMT5 by Virtual Screening and Biological Evaluation

作　　者：郑旭梅 郭超华 吴林韬[2] ZHENG Xumei;GUO Chaohua;WU Lintao(School of Chemistry and Materials Science,Shanxi Normal University,Taiyuan Shanxi 030000;Department of Chemistry,Changzhi University,Changzhi Shanxi 046011)

机构地区：[1]山西师范大学化学与材料科学学院,山西太原030000 [2]长治学院化学系,山西长治046011

出　　处：《长治学院学报》2024年第5期55-61,共7页Journal of Changzhi University

基　　金：山西省科技创新人才团队资助项目(202204051001034)。

摘　　要：蛋白质精氨酸甲基转移酶5(PRMT5)是Ⅱ型PRMTs的重要成员之一,其过表达与癌症的发生和发展密切相关,是肿瘤治疗的一种重要靶点。为了得到新型PRMT5底物竞争性抑制剂,文章基于受体PRMT5与配体EPZ015666的晶体复合物结构(PDB ID:4X61),对Specs和ChemDiv化合物库进行虚拟对接、药效团模型的建立与筛选,Lipinski和ADMET筛选,对选中的12个化合物进行PRMT5酶活测试。结果表明:化合物E749-0026和Y512-7443在1μM浓度下对PRMT5的抑制活性明显优于其他被测化合物;分子对接显示,两者与PRMT5之间通过氢键、静电作用力及疏水作用相结合。化合物E749-0026和Y512-7443可作为PRMT5底物竞争性抑制剂的先导化合物用于进一步研究。Protein arginine methyltransferase 5(PRMT5)is one of the important members of type II PRMTs,and its overexpression is closely related to cancer development and progression,which is an important target for tumor therapy.In order to obtain novel substrate-competitive inhibitors for PRMT5,the Specs and ChemDiv compound libraries were screened through virtual docking,pharmacophore modeling and screening,Lipinski and ADMET screening based on the crystal complex structure of the receptor PRMT5 with the ligand EPZ015666(PDB ID:4X61).The PRMT5 enzyme activity test was performed for the selected 12 compounds.The results showed that compounds E749-0026 and Y512-7443 exhibited significantly better inhibitory activities against PRMT5 than the other tested compounds at a concentration of 1μM;molecular docking showed that these two compounds bind to PRMT5 through hydrogen bonding,electrostatic forces and hydrophobic interactions.Compounds E749-0026 and Y512-7443 can be used as lead compounds for further studies as substrate-competitive inhibitors for PRMT5.

关 键 词：PRMT5 药效团 虚拟筛选 分子对接 底物竞争性抑制剂 

分 类 号：R914[医药卫生—药物化学]