基于网络药理学和分子对接法探索化湿败毒方治疗COVID-19的分子机制研究

The Molecular Mechanism of Huashi Baidu Decoction in the Treatment of COVID-19 Based on Network Pharmacology and Molecular Docking Technology

目的利用网络药理学和分子对接技术方法探索"化湿败毒方"抗新型冠状病毒肺炎(CoronaVirus Disease 2019,COVID-19)的分子机制。方法通过多个在线中药数据库检索化湿败毒方中14味中药的归经、化学成分和作用靶点。通过STRING数据库对化湿败毒方药物靶标和疾病靶标之间靶蛋白相互作用关系进行分析并通过Circos Tableviewer、Cytoscape软件进行药物-归经网络、药物-靶点网络和药物靶向蛋白-疾病蛋白(PPI)等网络的构建。接着通过Fun Rich和DAVID数据库进行基因本体(GO)功能富集分析并基于京都基因与基因组百科全书(KEGG)富集分析,通过在线绘图软件Omic Share进行可视化。最后运用CB-Dock分子对接网站软件对新型冠状病毒(SARS-Co V-2)的3CL水解酶(Mpro)以及宿主蛋白ACE2和类药性>0.8的活性成分分别进行对接分析。结果研究发现,化湿败毒方14味中药里有10味中药都相对特异性的归属于肺经,从复方中共筛选出来240个符合标准的化学成分,主要包括常见化合物如黄酮类化合物槲皮素(quercetin)和木犀草素(luteolin)、醇类化合物如豆甾醇(stigmasterol)和β-谷甾醇(beta-sitosterol)以及有机酸如没食子酸(gadelaidic acid)等。其它成分还有酯类、酰胺类和萜类等化学成分;通路富集分析表明,候选靶标富集的通路主要包括与癌症相关的多条通路、B细胞受体信号通路、Toll样受体信号通路、T细胞受体信号通路、HIF-1信号通路、TGF-beta信号通路等;分子对接结果显示,化湿败毒方中kanzonol F、xambioona dehydroeburicoic acid、cavidine等成分与SARS-Co V-23CL水解酶和ACE2均有较好的亲和作用。结论本文运用网络药理学和分子对接的方法初步探索了化湿败毒方可能通过多成分作用于病毒复制相关靶点和关键宿主蛋白,进而调节机体免疫和代谢通路等多种途径,最后发挥预防和治疗COVID-19的药效作用。

Objective To explore the molecular mechanism of Huashi Baidu Decoction against the novel coronavirus pneumonia(Corona virus disease 2019,COVID-19)by means of network pharmacology and molecular docking technology.The meridian,chemical composition and target of 14 Chinese herbal medicines in Huashi Baidu prescription were retrieved by searching multiple online Chinese medicine database analysis platforms.Methods Through the STRING database,the interaction relationship between the drug target and the disease target was analyzed and then the drug-meridian network and drug-target network were constructed through Circos Tableviewer and Cytoscape software.Subsequently,GO and KEGG enrichment analysis were performed through Fun Rich and DAVID databases to predict its mechanism of action,and visualization was achieved through online software OmicShare.Finally,the CB-Dock molecular docking software was used to perform docking of the new coronavirus(SARS-CoV-2)3 CL hydrolase(Mpro)and its host protein ACE2 with the active ingredients of Huashi Baidu Decoction whose drug-like score were greater than 0.8.Results The study found that 10 of the 14 Chinese medicinals in Huashi Baidu Decoction were relatively specific and belonged to the lung meridian.A total of 240 chemical components that met the standard were screened from the compound,including common compounds such as flavonoids,taking quercetin and luteolin for example,alcohol compounds including stigmasterol andβ-sitosterol,and organic acids such as gadelaidic acid.Other components include esters,amides and terpenes,etc.In addition,it is predicted that the relevant targets of 14 Chinese herbal medicines and COVID-19 are 1412 and 60,respectively.Pathway enrichment analysis showed that the candidate targets mainly involve in multiple pathways related to cancer,B cell receptor signaling pathway,Toll-like receptor signaling pathway,T cell receptor signaling pathway,HIF-1 signaling pathway,TGF-beta signaling pathway,etc.Molecular docking results show that kanzonol F,xambioona,dehydroeburicoic acid and cavidine have good affinity with SARS-CoV-23 CL hydrolase and ACE2.Conclusion In this paper,we have used network pharmacology and molecular docking methods to explore the possible effects of Huashi Baidu Decoction on the prevention and treatment of COVID-19 through multiple components acting on viral replication-related targets and key host proteins,and then modulating the immune and metabolic pathways of the body.