基于网络药理学和分子对接技术的金振口服液干预新型冠状病毒肺炎(COVID-19)的作用机制研究  

Investigate mechanism of Jinzhen Oral Liquid for prevention COVID-19 based on network pharmacology and molecular docking technology

作　　者：陶晓倩[1,2] 柯志鹏[1,2] 张新庄[1,2] 邓奕[1,2] 曹泽彧[1,2] 曹亮[1,2] 王振中[1,2] 肖伟[1,2] TAO Xiao-qian;KE Zhi-peng;ZHANG Xin-zhuang;DENG Yi;CAO Ze-yu;CAO Liang;WANG Zhen-zhong;XIAO Wei(Jiangsu Kanion Pharmaceutical Co.,Ltd.,Lianyungang 222001,China;State Key Laboratory of New-tech for Chinese Medicine Pharmaceutical Process,Lianyungang 222001,China)

机构地区：[1]江苏康缘药业股份有限公司,江苏连云港222001 [2]中药制药过程新技术国家重点实验室,江苏连云港222001

出　　处：《中草药》2020年第9期2326-2333,共8页Chinese Traditional and Herbal Drugs

基　　金：国家“重大新药创制”科技重大专项:现代中药创新集群与数字制药技术平台(2013ZX09402203)。

摘　　要：目的通过网络药理学及分子对接技术预测金振口服液(Jinzhen Oral Liquid,JOL)干预新型冠状病毒肺炎(COVID-19)的作用机制。方法通过文献挖掘以及DisGeNET、OMIM、KEGG、UniProt数据库联用检索与COVID-19相关的蛋白靶点。借助Traditional Chinese Medicine Network(TCMN)信息平台检索JOL中的化合物,运用Cytoscape3.2.1构建药材-化合物-靶点网络来预测JOL治疗COVID-19的活性成分及作用靶点。在RCSBPDB数据库中检索获取新型冠状病毒(SARS-CoV-2)3CL水解酶(3CLpro)和血管紧张素转化酶Ⅱ(ACE2)的晶体结构,借助AutoDock Vina软件将活性化合物与2个蛋白进行分子对接。结果药材-化合物-靶点网络包含异甘草酸内酯、贝母辛、番泻苷B等75个化合物分别来自甘草、大黄和平贝母3味药材,哺乳动物雷帕霉素靶蛋白(m TOR)、Janus激酶3(JAK3)、丝裂原活化蛋白激酶激酶1(MEK1)等28个靶点。网络特征分析阐明了JOL治疗COVID-19的9个关键化合物(异甘草酸内酯、甘草内酯、去氢鄂贝定碱、desoxo-glabrolid-acetate、贝母辛、贝母素乙、乌苏里啶酮、西贝素和euchrenone A5)以及10个潜在作用靶(m TOR、JAK3、ACE2、TNFA、AKT2、PIK3CA、MEK1、BRD2、ACE、ANPEP)。分子对接显示,JOL中部分活性化合物对3CLpro和ACE2蛋白具有一定的亲和力。结论JOL可能是通过调节溴结构域包含蛋白2(Brd2)、氨肽酶N(CD13)和ACE2的表达以及干预PI3K/Akt、Jak-STAT、TNF和MAPK信号通路来遏制COVID-19细胞因子风暴的发生和发展,并与3CLpro结合抑制病毒复制,从而有可能对COVID-19有防治作用。Objective To investigate the mechanism of Jinzhen Oral Liquid(JOL)for prevention COVID-19 through network pharmacology and molecular docking technology.Methods The protein targets related to COVID-19 were searched by literature mining and retrieving in DisGeNET,OMIM,KEGG and UniProt databases.With the aid of Traditional Chinese Medicine Network Pharmacology Intelligent Information Platform(TCMN)searching JOL chemical components and targets,the"herb-compound-target network"was constructed using Cytoscape-3.2.1 software to predict the main active ingredients and action targets of JOL in the treatment of COVID-19.The crystal structure of novel coronavirus(SARS-CoV-2)3 CL hydrolase(3 CLpro)and angiotensin converting enzyme II(ACE2)was retrieved from the RCSB PDB database,and the active compounds were docked with the two proteins by using AutoDock Vina software.Results The herb-compound-target network contained 75 compounds including isoglabrolide,peimisine,and sennoside B,etc.,which are from the three medicinal materials of Glycyrrhiza uralensis,Rheum officinale,and Fritillaria ussuriensis,and 28 targets including mammalian target of rapamycin(mTOR),Janus kinase 3(JAK3)and mitogen-activated protein kinase 1(MEK1).Furthermore,nine key compounds(isoglabrolide,glabrolide,ebeiedinone,desoxoglabrolid-acetate,peimisine,verticinone,imperialine,ussuriedinone and euchrenone A5)and 10 potential targets(mTOR,JAK3,ACE2,TNFA,AKT2,PIK3 CA,MEK1,BRD2,ACE and ANPEP)of JOL were predicted for treating COVID-19 by network characteristic analysis.The molecular docking results showed that some core compounds of JOL had a certain degree of affinity for 3 CLpro and ACE2.Conclusion JOL may inhibit the occurrence and development of cytokine storm in COVID-19 by regulating the expression of Brd2,CD13,and ACE2 and interfering with the PI3 K/Akt,Jak-STAT,TNF and MAPK signaling pathways,and inhibit virus replication by binding with 3 CLpro,thus exerting a preventive or therapeutic effect on COVID-19.

关 键 词：金振口服液 新型冠状病毒 新型冠状病毒肺炎 网络药理学 分子对接技术 细胞因子风暴 血管紧张素转化酶Ⅱ PI3K/Akt信号通路 JAK-STAT信号通路 TNF信号通路 MAPK信号通路 异甘草酸内酯 甘草内酯 去氢鄂贝定碱 贝母辛 贝母素乙 乌苏里啶酮 西贝素 

分 类 号：R285.5[医药卫生—中药学]