基于分子对接技术筛选新型冠状病毒变异体XBB.1.5 RBD抑制剂  

Screening for the novel coronavirus variant XBB.1.5 RBD inhibitors through molecular docking

作　　者：吕瑞杰 王晨宇 唐梦佳 吕旭东 杨兆勇[2] 张志斐 LYU Rui-jie;WANG Chen-yu;TANG Meng-jia;LYU Xu-dong;YANG Zhao-yong;ZHANG Zhi-fei(School of Pharmacy,North China University of Science and Technology,Tangshan 063210,China;Department of Microbial Metabolism Engineering,Institute of Medicinal Biotechnology,Chinese Academy of Medical Sciences&Peking Union Medical College,Beijing 100050,China)

机构地区：[1]华北理工大学药学院,唐山063210 [2]中国医学科学院北京协和医学院医药生物技术研究所微生物代谢室,北京100050

出　　处：《中国医药生物技术》2024年第4期308-314,共7页Chinese Medicinal Biotechnology

基　　金：国家自然科学基金面上项目(82373767);中国医学科学院中央级公益性科研院所基本科研业务费(2022-RW180-01)。

摘　　要：目的利用虚拟筛选技术筛选出可抑制新冠病毒变异体XBB.1.5 S蛋白受体结合区域(RBD蛋白)与血管紧张素转化酶2(ACE2)结合的小分子抑制剂,从而阻断新冠病毒对宿主的识别。方法在Mcule小分子数据库中下载486387个配体小分子。使用Jarvis-Patrick聚类后采用AutoDock Vina软件进行基于质心的分子对接。结果确定了XBB.1.5 RBD蛋白与ACE2相互作用的关键氨基酸残基,深入分析了5个候选物小分子与XBB.1.5 RBD蛋白的结合模式,化合物1与XBB.1.5 RBD蛋白的TYR489和SER490残基形成π-π堆积和氢键相互作用;化合物2与TYR449、SER494和TYR501通过氢键和π-π堆积结合;化合物3主要与TYR451形成氢键;化合物4与TYR427通过π-π堆积结合;化合物5则与ARG381、GLN387和ASN395残基形成π-阳离子堆积和氢键。上述相互作用均干扰了XBB.1.5 RBD与ACE2的结合,起到抑制作用。通过ADMET模拟分析,预测了候选化合物的生物利用度、遗传毒性和致癌性,最终得到了潜在的抑制剂分子。结论从数据库中筛选出潜在的新型冠状病毒变异体XBB.1.5 RBD蛋白的小分子结构,进而阻断S蛋白与ACE2之间的结合,为抗新型冠状病毒药物研究及处方筛选提供参考。Objective Virtual screening techniques was used to identify small-molecule inhibitors that can disrupt the interaction between the receptor-binding domain(RBD)protein on the S protein of the novel coronavirous XBB.1.5 variant and angiotensin-converting enzyme 2(ACE2),thereby impeding the novel coronavirus's recognition of the host.Methods We retrieved 486387 ligand small molecules from the Mcule small molecule database.Subsequently,we conducted centroid-based molecular docking using the AutoDock Vina software,following the Jarvis-Patrick clustering.Results Key amino acid residues involved in the interaction between the XBB.1.5 RBD protein and ACE2 were identified.An in-depth analysis of the binding modes of five candidate small molecules with the XBB.1.5 RBD protein revealed that compound 1 formedπ-πstacking and hydrogen bond interactions with TYR489 and SER490;compound 2 bond to TYR449,SER494,and TYR501 through hydrogen bonds andπ-πstacking;compound 3 primarily formed hydrogen bonds with TYR451;compound 4 interacted with TYR427 viaπ-πstacking;and compound 5 formedπ-cation stacking and hydrogen bonds with ARG381,GLN387,and ASN395 residues.These interactions disrupted the binding of the XBB.1.5 RBD to ACE2,thereby exerting an inhibitory effect.Additionally,the ADMET properties of the candidate compounds were simulated to predict their bioavailability,genotoxicity,and carcinogenicity,ultimately identifying potential inhibitor molecules.Conclusion Potential small molecule binders for the novel coronavious variant XBB.1.5 RBD protein are screened from the database.This aims are to hinder the binding between the S protein and ACE2,providing a reference for research and prescription screening in the fight against the novel coronavirus(SARS-CoV-2).

关 键 词：变异体XBB.1.5 新型冠状病毒 S蛋白 受体结合区域 分子对接 虚拟筛选 

分 类 号：R914[医药卫生—药物化学]