摘要
目的:基于网络药理学及分子对接技术探讨香连片对新型冠状病毒肺炎(Corona Virus Disease 2019, COVID-19)的作用机制。方法:通过中药系统药理学数据库与分析平台(Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform, TCMSP)、PubChem数据库、生物信息学分析工具(a bioinformatics analysis tool for molecular mechanism of traditional Chinese medicine, BATMAN-TCM)及SwissTarget Prediction平台查询香连片活性成分及其对应的靶点基因;根据大于2倍中位数的节点度值(degree)为条件,筛选香连片关键活性成分,并运用Cytoscape 3.6.1软件绘制关键活性成分-对应靶点网络;通过GeneCards及PHARMGKB疾病数据库,以"coronavirus pneumonia"、"COVID-19"及"SARS-CoV-2"为关键词进行检索疾病靶点基因。运用Cytoscape 3.6.1软件进行交集,得到共同靶点并构建成分-靶点-疾病网络图;通过STRING网站对共同靶点构建蛋白相互作用(Protein Protein interaction, PPI)网络,通过DAVID数据库对共同靶点进行基因本位(gene ontology, GO)和京都基因与基因组百科全书(Kyoto encyclopedia of genes and genomes, KEGG)分析;利用CB-Dock网站对筛选出的活性成分及抗病毒化药和SARS-CoV-2 3CL水解酶及血管紧张素转化酶Ⅱ (angiotensin converting enzyme Ⅱ, ACE2)进行分子对接。结果:香连片共得到41个活性成分,其中16个关键活性成分,并与疾病靶点相交得到24个共同靶点;GO功能富集得到分子功能(molecular function, MF)、细胞组分(cellular component, CC)及其所参与的生物过程(biological process, BP)分别为125条、16条及24条;KEGG富集得到94条通路,其通路多与免疫反应和炎症反应有关,主要有PI3K-Akt、Ras、HIF-1、MAPK、NF-kB以及TNF等信号通路;分子对接得出黄柏酮、氧化小檗碱、吴茱萸碱、吴茱萸次碱及豆甾醇等多种成分与SARS-CoV-2 3CL水解酶及ACE2的对接亲和力均强于2种临床化学药物(阿比多尔及利巴韦林)。结论:香连片多是通过作用于MAPK家族、IL1B、NFKB1、CASP3、CCL5、TNF等靶点因子来调节PI3K-Akt、MAPK、NF-kB及TNF等炎症免疫通路,以多成分、多靶点、多途径参与COVID-19的多种生理过程,从而对COVID-19有一定治疗作用;在中药成分上,黄柏酮、氧化小檗碱、吴茱萸碱、吴茱萸次碱、豆甾醇、吴茱萸酰胺类成分等可以很好作用于COVID-19治疗中涉及到的2种关键酶(SARS-CoV-2 3CL水解酶及ACE2),故这几种中药单体成分有作为治疗COVID-19的新药潜能。
OBJECTIVE Network pharmacology and molecular docking technology were used to explore the mechanism of Xianglian Tablets in the treatment of COVID-19(Corona Virus Disease 2019).METHODS Active components and corresponding target genes were investigated by Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform(TCMSP), PubChem database, a Bioinformatics Analysis Tool for Molecular mechANism of Traditional Chinese Medicine(BATMAN-TCM) and SwissTarget Prediction platform. According to the node degree value(Degree) greater than 2 times median, the key active components were screened and Cytoscape 3.6.1 software was utilized for drawing the key active component-corresponding target network. Through GeneCards and PHARMGKB disease database, disease target genes were retrieved with "Coronavirus pneumonia", "COVID-19" and "SARS-COV-2" as keywords. Cytoscape 3.6.1 software was employed for intersection to obtain common targets and construct component-target-disease network diagram. Protein Protein interaction(PPI) network was constructed for common targets through STRING website and gene ontology(GO) analysis and Kyoto encyclopedia of genes and genomes(KEGG) analysis were performed for common targets through DAVID database. CB-Dock website was utilized for combining bioactive compounds and antiviral drugs with SARS-CoV-2 3 CL hydrolase and angiotensin converting enzyme Ⅱ(ACE2).RESULTS A total of 41 active components were obtained from Xianglian Tablets, including 16 key active components and 24 common targets were obtained when intersecting with disease targets. The biological process(BP), cell composition(CC) and molecular function(MF) were 125, 16 and 24 respectively by GO functional enrichment analysis. And 94 pathways were screened by KEGG enrichment, most of which were related to immune response and inflammatory response, mainly including PI3 K-Akt, Ras, HIF-1, MAPK, NF-KB and TNF. Molecular docking results indicated that the docking affinity of obacunone, berlambine, evodiamine, rutaecarpine and stigmasterol with(SARS-COV-2) 3 CL hydrolase and ACE2 were stronger than that of arbidol and ribavirin.CONCLUSION Xianglian Tablets regulate PI3 K-Akt, MAPK, NF-kB, TNF and other inflammatory and immune pathways by acting on target factors such as MAPK family, IL1 B, NFKB1, CASP3, CCL5, and TNF. It participates in various physiological processes of COVID-19 with multiple components, multiple targets and multiple channels so as to have a certain therapeutic effect on COVID-19. As for the components of traditional Chinese medicine, obacunone, berlambine, evodiamine, rutaecarpine, stigmasterol and evodiaamides can well act on the two key enzymes involved in the treatment of COVID-19 so that these monomeric components of traditional Chinese medicine are potentially new therapeutic drugs for COVID-19.
作者
董悦
李竣
佟海英
黄先菊
Awais Ihsan
DONG Yue;LI Jun;TONG Hai-ying;HUANG Xian-ju;Awasi Ihsan(College of Pharmacy,Southcentral University for Nationalities,Hubei Wuhan 430074,China;Institute of Traditional Chinese Medicine,Beijing University of Chinese Medicine,Beijing 100029,China;Department of Biosciences,COMSATS University Islamabad(CUI),Sahiwal,Pakistan)
出处
《中国医院药学杂志》
CAS
北大核心
2021年第7期667-674,686,共9页
Chinese Journal of Hospital Pharmacy
基金
中医药现代化研究重点研发计划项目(编号:2017YFC1701004)
中央高校基本科研业务费专项资金资助项目(编号:CZP20002)。
作者简介
董悦,女,在读硕士,研究方向:民族药有效性与安全性;通讯作者: 黄先菊,女,博士,教授,研究方向:民族药有效性与安全性。
