基于网络药理学和分子对接探讨六神胶囊治疗COVID-19的物质基础及作用机制
Study on the Potential Material Basis and Molecular Mechanism of Liushen Capsule on the Treatment of COVID-19 Through the Network Pharmacology and Molecular Docking
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摘要: 目的 通过网络药理学及分子对接技术探寻六神胶囊治疗新型冠状病毒肺炎（COVID-19）的潜在物质基础和分子机制。方法 借助常用的网络药理学数据库检索六神胶囊中雄黄、人工牛黄、冰片、蟾酥和麝香等的有效活性成分和作用靶点。通过UniProt数据库查询靶点对应的基因，Cytoscape 3.6.1软件构建中药-有效活性成分-有效靶点网络，通过Metascape平台进行GO富集分析、KEGG和Reactome信号通路分析，将中药有效活性成分-有效靶点网络中排名前20的单体与新型冠状病毒（SARS-CoV-2）3CL水解酶、血管紧张素转化酶Ⅱ（ACE2）以及SARS-CoV-2 RNA依赖性RNA聚合酶（RNA dependent RNA polymerase， RdRp）进行分子对接。结果 中药-有效活性成分-有效靶点网络包含药材5个、化合物132个、靶点2 082个，关键靶点涉及PTGS2、ESR1、PLA2G1B、PTGS1等。GO功能富集分析得到GO条目495个（P<0.05），其中生物过程（BP）条目287个，细胞组成（CC）条目96个，分子功能（MF）条目112个。KEGG通路富集筛选得到107条信号通路（P<0.05），主要涉及免疫和炎症通路，细胞生长、代谢、凋亡相关通路，癌症通路，神经活性配体-受体相互作用等。Reactome通路富集筛选得到85条信号通路（P<0.05），主要涉及G蛋白偶联、白细胞介素信号、受体酪氨酸激酶信号、神经系统、基因转录等通路。分子对接结果显示六神胶囊中麦角胺、熊果酸、鹅去氧胆酸等核心活性化合物与SARS-CoV-2 3CL水解酶、ACE2以及SARS-CoV-2 RdRp的亲和力与临床推荐化学药相似。结论 六神胶囊中的活性成分麦角胺、熊果酸、鹅去氧胆酸等可能通过与ACE2结合并作用于PTGS2、ESR1、PLA2G1B和PTGS1等靶点调节多条信号通路，从而起到抑制SARS-CoV-2的作用。Abstract: OBJECTIVE To explore the potential material basis and molecular mechanism of Liushen Capsule on inhibiting COVID-19 through network pharmacology and molecular docking technology. METHODS The effective monomers and targets of realgar， calculus bovis artifacts， borneolum， bufonis venenum and moschus in Liushen Capsule were searched with the help of the network pharmacology databases. Based on UniProt database and Cytoscape 3.6.1 software， the gene corresponding to the target was queried， and the network of traditional Chinese medicine-effective ingredients-effective target was constructed. GO， KEGG， Reactome enrichment analysis were carried out by Metascape platform to predict the mechanism of action. Molecular docking of the top 15 monomers was carried out in the medicinal material-compound-target network with SARS-CoV-2 3CL hydrolase， angiotensin-converting enzyme Ⅱ (ACE2)， and SARS-CoV-2 RNA dependent RNA polymerase (RdRp). RESULTS The network of TCM-active ingredients-effective targets included 5 herbs， 136 compounds and 2 082 targets. The key targets were PTGS2、ESR1、PLA2G1B and PTGS1. The function enrichment analysis of GO was 495 (P<0.05)， of which there were 287 biological processes (BP)， and 96 related items of cell composition (CC)， and 112 molecular function (MF) items. There were 107 signal pathways (P<0.05) in the KEGG pathway enrichment screening， which mainly involved cancer pathway， neuroactive ligand receptor interaction， cell growth， metabolism， apoptosis related pathway， immunity and inflammation. There were 85 signal pathways (P<0.05) in the Reactome pathway enrichment screening， which were mainly involved in nervous system， G protein coupling， interleukin signal， receptor tyrosine kinase signal and gene transcription. The results of molecular docking showed that the affinity of ergotamine， ursolic acid， chenodeoxycholic acid and other core active compounds in Liushen Capsule with SARS-CoV-2 3CL and ACE2 was similar to that of clinically recommended chemicals. CONCLUSION The active compounds in Liushen Capsule， ergotamine， ursolic acid and chenodeoxycholic acid， may regulate multiple signal pathways by binding to ACE2 to act on targets such as PTGS2， ESR1， PLA2G1B and PTGS1， thereby inhibit SARS-CoV-2.
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