基于网络药理学和分子对接技术探讨四逆散治疗Graves病的作用机制

To explore the mechanism of Sinisan in treatment of Graves'disease based on network pharmacology and molecular docking technology

目的利用网络药理学方法和分子对接技术探索四逆散治疗毒性弥漫性甲状腺肿(Graves)病的潜在活性成分、作用靶点和代谢通路,为四逆散治疗Graves病的临床应用和深入阐明四逆散干预Graves病的作用机制提供理论参考。方法运用TCMSP平台及查阅文献筛选四逆散的主要活性成分及作用靶点。以“Graves’disease”为关键词,挖掘GeneCards、CTD、DisGeNET、OMIM、TTD和DrugBank数据库中Graves病的相关靶点。利用Cytoscape软件构建“中药–成分–靶点–疾病”网络,运用String平台构建蛋白互相作用(PPI)网络。运用Metascape平台对共同靶点通过GO数据库和KEGG数据库进行注释和富集分析。在RCSB PDB和PubChem数据库中获得成分和靶点的结构,利用pymol软件和autodock vina软件进行分子对接。结果四逆散治疗Graves病的主要活性成分可能为槲皮素、山柰酚、芹菜素、异鼠李素、柚皮素、异甘草素、木犀草素、葛根素等,PPI网络中关键靶点为AKT1、TNF、INS、IL6、VEGFA、TP53、JUN、CASP3、IL1B、MAPK3等。GO与KEGG分析主要代谢通路可能有PI3K-Akt信号通路、TNF信号通路、IL-17信号通路、HIF-1信号通路、p53信号通路、细胞凋亡、Th17细胞分化、Toll样受体信号通路、甲状腺激素信号通路、VEGF信号通路等。四逆散治疗Graves病的作用机制可能有调节免疫失衡、抑制细胞增殖和促进凋亡、抗氧化应激、抑制甲状腺血管新生和减轻外周组织器官损伤等。分子对接结果显示四逆散主要成分与治疗Graves病的关键靶点结合活性较高且对接构象较稳定。结论四逆散可能通过多成分、多靶点影响多条代谢通路发挥治疗Graves病的作用,为四逆散治疗Graves病的作用机制实验研究提供参考。

Objective The potential active components,action targets and metabolic pathways of Sinisan in treatment of Graves'disease were explored by using network pharmacology and molecular docking technology,so as to provide theoretical reference for the clinical application of Sinisan in treatment of Graves'disease and further elucidation of the mechanism of action of Sinisan in the intervention of Graves'disease.Methods The main active components and targets of Sinisan were screened by TCMSP platform and literature review.With“Graves'disease”as the key word,the related targets of Graves'disease were extracted from GeneCards,CTD,DisGeNET,OMIM,TTD and DrugBank databases.Cytoscape software was used to construct the network of“TCM-component-target-disease”,and String platform was used to construct PPI network.Metascape platform was used to annotate and enrich common targets through GO database and KEGG database.The structures of components and targets were obtained from RCSB PDB and PubChem databases,and molecular docking was performed using Pymol software and Autodock Vina software.Results The main active ingredients of Sinisan in treatment of Graves'disease may be quercetin,kaempferol,apigenin,isornetin,naringin,isorritin,luteolin,puerarin,etc.The key targets in PPI network are AKT1,TNF,INS,IL-6,VEGFA,TP53,JUN,CASP3,IL-1B,MAPK3,etc.The main metabolic pathways analyzed by GO and KEGG may include PI3K-Akt signaling pathway,TNF signaling pathway,IL-17 signaling pathway,HIF-1 signaling pathway,p53 signaling pathway,apoptosis,Th17 cell differentiation,Toll-like receptor signaling pathway,thyroid hormone signaling pathway,VEGF signaling pathway,etc.The mechanism of Sinisan in treating Graves'disease may include regulating immune imbalance,inhibiting cell proliferation and promoting apoptosis,resisting oxidative stress,inhibiting thyroid angiogenesis and alleviating peripheral tissue and organ injury.The molecular docking results showed that the main active components of Sinisan had high binding activity and stable docking conformation with the key target of Graves'disease.Conclusion Sinisan may affect multiple metabolic pathways through multiple components and multiple targets,which can provide reference for experimental study on the mechanism of action of Sinisan in the treatment of Graves'disease.