基于网络药理学的新型冠状病毒肺炎核心中药靶标预测及其作用机制研究

The Study on the Mechanism and Target Prediction of Core Herbs of COVID-19 Based on Network Pharmacology

目的:筛选治疗新型冠状病毒肺炎(Corona Virus Dsease 2019,COVID-19)处方中核心中药的活性分子及其潜在靶标,进一步分析其作用机制。方法:应用Microsoft Excel筛选2020年2月安徽省省级中医专家组及阜阳市中医医院派驻阜阳市第二人民医院参与治疗COVID-19的专家开具的处方中的核心中药;利用中药系统药理学数据库与分析平台(traditional Chinese medicine systems pharmacology da-tabase and analysis platform,TCMSP)过滤中药活性分子及相应靶标,从人类基因数据库(the human gene database,GeneCards)、人类孟德尔遗传数据库(online mendelian inheritance in man,OMIM)寻找COVID-19的相关基因,选取其与中药靶基因的交集,预测中药治疗COVID-19的潜在靶标;使用Cytoscape软件构建中药调控网络图;利用蛋白互作网络(functional protein association networks,STRING)数据库构建潜在靶标的PPI蛋白互作网络,进一步对其中关键靶标进行基因本体(gene ontology,GO)功能富集及京都基因与基因组百科全书(Kyoto Encyclopedia of Genes and Genomes,KEGG)信号通路富集分析。结果:处方共使用中药136味,核心中药茯苓、甘草、陈皮、半夏为二陈汤组成药物;获得中药相关靶标223条,COVID-19相关基因364条,中药-“COVID-19”潜在靶标52条,其中核心靶标分别为胱天蛋白酶3(Caspase-3,CASP3)、白细胞介素6(interleukin-6,IL-6)、白细胞介素10(interleukin-10,IL-10)、重组人白细胞介素1β(recom-binant human IL1βprotein,IL-1β)、促分裂原活化蛋白激酶3(mitogen-activated protein kinase 3,MAPK3)、促分裂原活化蛋白激酶8(mitogen-activated protein kinase 8,MAPK8)、信号传导子和激活子3(signal transducers and activators of transcription 3,STAT3)、促分裂原活化蛋白激酶1(mitogen activated protein kinase 1,MAPK1)等,关键活性分子有黄芩苷、β-谷甾醇、柚皮素、川橙皮素、山奈酚、甘草查尔酮A、槲皮素等。结论:核心中药可能通过作用于白细胞介素17(interleukin-17,IL-17)、Toll样受体(Toll-like receptors,TLRs)、肿瘤坏死因子(tumor necrosis factor,TNF)、低氧诱导因子1等信号通路,参与调控细胞因子及炎症免疫介质、细胞凋亡、氧化应激等环节,从而发挥对COVID-19的防治作用。

Objective:To screen the active molecules of core herbs in the prescriptions of treating COVID-19 and its potential targets,and further analyze its mechanism.Methods:Microsoft Excel was used to screen the core herbs in the prescriptions prescribed by the experts accredited to Fuyang city the second people's hospital by Anhui provincial TCM expert group and Fuyang city Hospital of TCM,who participated in the treatment of COVID-19;TCMSP platform was adopted to filter active molecules of core herbs and its potential targets,COVID-19-related genes were explored from Gene Cards and OMIM databases to take the intersection with target gene of herbs,and predict the potential targets of herbs in the treatment;Cytoscape software was used to construct network control chart of herbs;STRING database was applied to construct PPI protein interaction network of the potential targets,to further analyze enrichment of GO function and KEGG signaling pathway of the key targets.Results:All 136 herbs were used in the prescriptions,core herbs Fuling(poria),Gancao(liquorice root),Chenpi(Citri Reticulatae Pericarpium)and Banxia(Pinelliae Rhizoma)were the ones of forming Erchen Tang;223 herbs-related targets were obtained,364 COVID-19-related genes,and 52 potential targets of herbs-COVID-19,among them,the core targets were CASP3,IL-6,IL-10,IL-1β,MAPK3,MAPK8,STAT3,MAPK1 and others;key active molecules contained baicalin,β-sitosterol,naringenin,hesperidin,kaempferol,glycyrrhizin chalcone a,quercetin,etc.Conclusion:Core herbs are involved in the regulation of cytokines,inflammatory immune mediators,apoptosis and oxidative stress,therefore to develop the preventive effects for COVID-19 possibly through acting on the signaling pathway of IL-17,TLRs,TNF,hypoxia inducible factor-1 and others.