基于网络药理学及分子对接技术探讨初期复方治疗新型冠状病毒肺炎分子机制

Study of Molecular Mechanism of Preliminary Formula on Corona Virus Disease 2019 Based on Network Pharmacology and Molecular Docking Technology

目的基于网络药理学和分子对接技术探讨初期复方中多种药物成分之间协同增效治疗新型冠状病毒肺炎的机制。方法运用中药系统药理学数据库及分析平台(TCMSP)收集初期复方活性成分和药物靶点,通过Genecards、pharmGKB、DisGeNET数据库收集新型冠状病毒肺炎的相关靶点。将药物-疾病交集靶点导入Cytoscape 3.7.2软件的Bisogenet插件构建蛋白-蛋白相互作用网络(PPI)。利用Cytoscape 3.7.2软件构建初期复方“潜在活性成分-疾病靶点”网络。通过R软件对交集靶蛋白进行基因本体(gene ontology,GO)功能富集分析及京都基因与基因组百科全书(kyoto encyclopedia of genes and genomes,KEGG)通路富集分析。并对所选靶蛋白和所选化合物进行分子对接。结果得到54个药物活性成分和225个药物靶点,其中药物疾病共同作用靶点41个。GO富集分析显示细胞对生物刺激的反应、对脂多糖的反应、对细菌来源分子的反应等生物过程,KEGG通路主要涉及白细胞介素-17(interleukin-17,IL-17)通路、肿瘤坏死因子(tumor necrosis factor,TNF)等信号通路。分子对接结果表明初期复方化合物与靶蛋白展现出较好的结合活性。结论该研究表明初期复方具有多成分、多靶点、多途径的特点,涉及多条信号通路及生物学过程,其关键活性成分槲皮素、木犀草素、汉黄芩素、山柰酚、川陈皮素可能通过与核心靶蛋白(NTRK1、TP53、EGFR)、ACE2、3CLpro相结合抑制内毒素脂多糖的释放,抑制过度活跃TNF通路、IL-17信号通路;抗氧化,清除自由基;改变病毒复制环境,阻断病毒进入宿主细胞等机制发挥对新冠肺炎的治疗作用。

Objective To study the mechanism of synergistic efficacy of multiple drug components of the preliminary formula in the treatment of corona virus disease 2019(COVID-19)based on network pharmacology and molecular docking.Methods Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform(TCMSP)database was used to collect the active components and the targets of the active compounds,Genecards database,pharmGKB database and DisGeNET database were used to collect the relevant targets of COVID-19.Then the common targets of drugs and diseases were imported into Cytoscape3.7.2 software to construct the PPI network.“Potential compounds-disease target”network was constructed by Cytoscape 3.7.2 software.The Gene Ontology(GO)functional enrichment analysis of the intersection proteins was performed using R software,and the enrichment analysis of the Kyoto Encyclopedia of Genes and Genomes pathways was conducted.At the same time,molecular docking verification was carried out.Results 54 active compounds and 225 drug targets were screened,which 41 were the common targets of drugs and diseases.GO enrichment analysis showed that cell response to biological stimulation,reaction to LPS,reaction to bacteria-derived molecules and other biological processes,and KEGG pathway was mainly involved in interleukin-17(IL-17)pathway,tumor necrosis factor(TNF)pathway and other signaling pathways.The results of molecular docking showed that the preliminary formula showed good binding activity with the target protein.Conclusion The preliminary formula has multiple components,multiple targets,the characteristics of the multi-channel,involving multiple signaling pathways and the biological process,the key active ingredients quercetin,luteolin,wogonin,kaempferol,nobiletin may combine with core target proteins(NTRK1,TP53,EGFR),ACE2,and 3 CLpro to inhibit the release of endotoxin lipopolysaccharide,inhibit excessive TNF,IL-17 signal pathways in active;Anti-oxidation,scavenging free radicals;blocking virus entry into huaman cells have potential therapeutic effects on COVID-19.