基于虚拟筛选方法从化合物数据库中筛选SARS-COV-2的2’-O-甲基转移酶抑制剂  

Discovery of SARS-CoV-22’-O-methyltransferase(NSP16)inhibitors from compound database based on virtual screening

作　　者：储晓慧 宋昱 温泽宇 王晓雨 于宗霞[1] CHU Xiao-hui;SONG Yu;WEN Ze-yu;WANG Xiao-yu;YU Zong-xia(College of Life Sciences and Biotechnology,Dalian University,Dalian 116622,China)

机构地区：[1]大连大学生命科学与技术学院,辽宁大连116622

出　　处：《化学研究与应用》2022年第5期1016-1024,共9页Chemical Research and Application

基　　金：国家自然科学基金项目(31700267);植物分子遗传国家重点实验室和大连市青年科技之星项目资助(2017RQ025)。

摘　　要：由SARS-CoV-2病毒引起的新型冠状病毒肺炎COVID-19对世界各国的日常生活和卫生保健系统造成了前所未有的冲击,治疗该疾病的特效药仍在紧张的研制中。2’-O-甲基转移酶(nsp16)催化了SARS-COV-2的RNA“加帽”反应,是维持该病毒RNA稳定性的重要步骤,因此通过筛选nsp16的抑制剂,干扰SARS-COV-2的稳定性,具有一定的药物开发价值。Sinefungin是一种泛甲基转移酶抑制剂,对nsp16具有较好的抑制效果,被用作本文抑制剂筛选的阳性对照。首先依据RMSD值对分子动力学模拟过程中产生的nsp16-Sinefungin结合构象进行聚类分析,构建并优化药效团模型,该模型包含芳香特征R15、氢键供体特征D9、正电特征P14和负电特征N13各一个。随后利用该药效团模型进行小分子数据库筛选、分子对接、MM-GBSA结合自由能计算、分子动力学模拟,并对筛选得到的化合物进行成药性评价,最终得到C1(CAS:1224032-33-0)、C2(CAS:1224020-56-7)、C3(CAS:1224031-61-1)和C7(CAS:1224035-30-6)四个化合物。结果表明四个化合物均可稳定结合于nsp16活性口袋。The new type of coronavirus pneumonia COVID-19 caused by SARS-CoV-2 virus has resulted in unprecedented crises to the daily life and health care system all over the world,while the specific drugs for the treatment of this disease are still under intense development.2’-O-methyltransferase(nsp16)catalyzes the RNA"capping"reaction of SARS-COV-2,which is important for this virus to maintain its RNA stability.Therefore,screening inhibitors of nsp16 by interfering the stability of SARS-COV-2 has promising drug development value.Sinefungin is a pan-methyltransferase inhibitor which effectively inhibits nsp16’s activity and is used as a positive control for inhibitor screening in this article.According to the RMSD value,we first performed cluster analysis of the nsp16-Sinefungin conformation produced by the molecular dynamics simulation,and the representative structure was selected for constructing,merging and simplifying the pharmacophore model.The pharmacophore model consists of an aromatic ring R15,a hydrogen bond donor D9,a positive charge P14 and a negative charge N13.Then the selected compounds were evaluated by docking simulation,MM-GBSA free binding energy calculation,molecular dynamics simulation and their potential druggabilities.Finally,four compounds C1(CAS:1224032-33-0),C2(CAS:1224020-56-7),C3(CAS:1224031-61-1)and C4(CAS:1224035-30-6)were selected.The results show that these four compounds could stably bind to the key amino acids in the active pocket of nsp16.

关 键 词：SARS-CoV-2 2’-O-甲基转移酶 药效团 分子动力学 虚拟筛选 

分 类 号：Q555[生物学—生物化学]