基于网络药理学的小柴胡汤治疗新型冠状病毒肺炎(COVID-19)发热的可行性探讨

目的通过网络药理学和分子对接的方法,初步探讨小柴胡汤在新型冠状病毒肺炎(COVID-19)治疗中缓解发热及抗病毒的可能作用机制。方法运用网络药理学方法分析小柴胡汤治疗发热的潜在靶点及通路;从TCMSP、Pharm Mapper数据库收集小柴胡汤的成分和作用靶点;OMIM和Genecards数据库收集发热相关靶点;String数据库构建蛋白相互作用网络,分析核心靶点;DAVID数据库和KOBAS3.0进行基于基因本体论(GO)的功能富集分析和基于京都基因与基因组百科全书(KEGG)的通路富集分析;Cytoscape3.2.7构建成分-靶点-通路网络图。运用分子对接技术筛选与新型冠状病毒(SARS-CoV-2)以及SARS-CoV-2感染靶细胞关键受体血管紧张素转化酶Ⅱ(ACE2)结合力较强的活性成分,预测可能的结合位点。结果网络药理学分析表明,小柴胡汤共筛选出165种活性成分,预测到靶点168个,筛选出发热相关靶点7 006个,取交集得到小柴胡汤与发热相关的靶点141个。GO富集到基因功能292个,KEGG富集到基因通路30条。分子对接结果表明,小柴胡汤的主要活性成分与SARS-CoV-2和ACE2均有较强的结合能力,其中β-谷甾醇、豆甾醇和3′-羟基-4′-O-甲基葡萄糖苷为结合最强的3个有效成分。结论网络药理学方法初步探讨了小柴胡汤缓解COVID-19发热的作用机制,β-谷甾醇、豆甾醇和3′-羟基-4′-O-甲基葡萄糖苷可能为小柴胡汤中主要发挥抑制SARS-CoV-2的成分,为进一步的研究提供了方向。

Feasibility of Xiaochaihu Decoction on fever induced by coronavirus disease 2019 (COVID-19) based on network pharmacology

Objective The aim of this article was to study the potential antivirus and fever reducing mechanisms of Xiaochaihu Decoction (XCHD) on novel coronavirus pneumonia based on network pharmacology and molecular docking method. Methods Firstly, the potential targets and pathways of XCHD on fever were analyzed using network pharmacology. Compounds and potential targets in XCHD were screened using TCMSP and PharmMapper databases. The targets in fever reducing were identified from OMMI and Genecards databases. The protein-protein interaction network was established by String database to analyze key targets. The gene oncology (GO) analysis and Kyoto encyclopedia of genes and genomes (KEGG) analysis of key targets were also conducted to generate the relative pathways based on DAVID and KOBAS 3.0 databases, respectively. The compound-target-pathway network was established using Cytoscape 3.2.7. In addition, we used molecular docking method to identify the crucial compounds with higher connectivity on SARS-CoV-2 and the angiotensin-converting enzyme 2 (ACE2). ACE2 has been identified as the key target of SARS-CoV-2 entering cells. The possible binding sites of compounds on SARS-CoV-2 and ACE2 were predicted. Results Network pharmacology analysis indicated that 165 active compounds and 168 relative targets were selected. A total of 7006 targets related to fever were identified. In addition, 141 potential targets of XCH on fever were identified. Totally, 292 GO terms of XCHD on fever and 30 pathways were identified using GO and KEGG analysis. Furthermore, molecular docking indicated that main active compounds in XCHD exhibited higher affinity with both SARS-CoV-2 and ACE2. Beta-sitosterol, stigmasterol, 3''-hydroxy-4''-O-methylglabridin were top three candidates with highest affinity. Conclusion In summary, our study identified the potential mechanisms of XCHD on fever. Besides, Beta-sitosterol, stigmasterol, 3''-hydroxy-4''-O-methylglabridin could be the key compounds to exert anti-viral effects against SARS-CoV-2. Our prediction also provided the research fields to further study the mechanisms of XCH on SARS-CoV-2 infection in future.