融合“通路-靶点-活性成分”探讨藿朴夏苓汤治疗新冠肺炎炎症风暴的网络药理学机制与初证

Discussion on the Network Pharmacological Mechanism and Preliminary Evidence of Huopo Xialing Decoction for the Treatment of 2019-nCoV Inflammatory Storm by Integrating“Pathway-Target-Active Component”

目的采用网络药理学和分子对接技术探索藿朴夏苓汤治疗新冠肺炎炎症风暴的有效化合物成分和潜在机制。方法首先通过《中药大辞典》中获取藿朴夏苓汤的药性与归经,然后运用TCMSP、BATMAN-TCM、TCMID数据库,检索该复方各味药的有效成分和作用靶点。并将经过Uniprot数据库检索的靶基因官方名称及检索出的相应中药成分、中药名称输入Cyoscape3.7.1软件,使“药物-有效成分-靶点”网络可视化。其次,运用STRING平台和BioGPS平台获取药物关键靶点和基因表达的器官组织,构建“关键靶点-器官组织”网络图。然后,将藿朴夏苓汤关键基因和新冠肺炎炎症风暴的靶基因取交集,获取“药物-疾病”基因,并对其进行GO功能富集分析和KEGG通路富集分析,预测藿朴夏苓汤治疗新冠肺炎炎症风暴作用机制和主要有效化合物成分。最后对主要化合物成分运用Autodock Vina软件进行分子对接。结果“药物-有效成分-靶点”网络涉及10味中药、53个有效药物成分,210个靶基因;网络拓扑分析结果显示,有79个相互密切作用的关键基因,根据BioGPS基因定位显示,这些基因主要在肺、心、肝、心肌细胞、支气管上皮细胞、CD34+细胞等器官组织内高表达;按照P<0.05的标准,GO富集到细胞对细菌起源分子的反应、白细胞与细胞粘附的正调控、炎症反应的正调控等938个条目,KEGG富集到甲型流感、IL-17信号通路、Th17细胞分化、非小细胞肺癌等与新冠肺炎炎症风暴相关的130条信号通路;分子对接结果显示槲皮素、木犀草素、黄芩素、利卡灵A以及卡维丁等有效成分,具有和推荐药类似或更好的与ACE2受体、2019-nCoV spike glycoprotein结合的能力。结论藿朴夏苓汤的有效化合物成分槲皮素、木犀草素、黄芩素、利卡灵A以及卡维丁等能通过多脏器组织与ACE2结合,作用于RELA、CALM1、IL6、IL4、IL2、PRKCB、PRKCA、IL1B、CDK4、CCL2、CXCL10、EGFR等关键靶点参与的多条信号通路,从而发挥对新冠肺炎炎症风暴的治疗作用。

Objective To explore the effective compound components and potential mechanisms of Huopu Xialing Decoction for the treatment of inflammatory storm in 2019-nCoV using network pharmacology and molecular docking techniques.Methods First,the properties and meridian tropism of Huopu Xialing Decoction were obtained from the Dictionary of Chinese Medicine.Then,TCMSP,BATMAN-TCM and TCMID databases were used to search the effective components and target points of each compound medicine.The official name of the target gene,the corresponding Chinese medicine ingredients and the Chinese medicine names were retrieved from UniProt database and input into cyoscape 3.7.1 software to visualize the network of“medicine effective ingredients target”.Secondly,Secondly,the STRING platform and BioGPS platform were used to obtain the key targets and organ tissues for gene expression,and construct the“key target-organ tissue”network map.Then,the key genes of Huopu Xia Ling Tang and the target genes of New Crown Pulmonary Inflammatory Storm were intersected to obtain"drug-disease"genes,and GO functional enrichment analysis and KEGG pathway enrichment analysis were performed to predict the mechanism of action and the main active compound components of Huopu Xialing Decoction for 2019-nCoV inflammatory storm.Finally,Autodock Vina software was used to docking the main compounds.Results“Drug effective component target”network involved 10 traditional Chinese medicine,53 effective drug components and 210 target genes;network topology analysis results showed that there are 79 key genes that interacted closely with each other.According to BioGPS gene location,these genes were mainly expressed in lung,heart,liver,cardiac muscle cells,bronchial epithelial cells,CD34+cells and other organs and tissues;according to P<0.05 The novel coronavirus pneumonia is enriched by GO,which was enriched by 938 items,including cell response to bacterial origin,regulation of leukocyte to cell adhesion,and positive regulation of inflammation.KEGG is enriched into 130 signaling pathways related to influenza A,IL-17 signaling pathway,Th17 cell differentiation,non-small cell lung cancer,and other new inflammatory diseases.The molecular docking results showed that quercetin,luteolin,baicalein,and so on.Effective ingredients such as Ricarin A and Kavudine had the similar or better ability to bind to ACE2 receptor and 2019 ncov spike glycoprotein.Conclusion The active compound components of Huopo Xialing Decoction,such as quercetin,lignocaine,baicalin,Licarin A and carvacrol,can bind to ACE2 through multiple organ tissues and act on multiple signaling pathways involving key targets such as RELA,CALM1,IL6,IL4,IL2,PRKCB,PRKCA,IL1B,CDK4,CCL2,CXCL10,EGFR,thus exerting a therapeutic effect on the inflammatory storm of neocrown pneumonia.