基于网络药理学和分子对接探讨防己黄芪汤治疗肾性水肿的机制与通路

Mechanism and pathway of Fangji Huangqi Decoction in the treatment of nephritic edema based on network pharmacology and molecular docking

关键词:  防己黄芪汤  肾性水肿  网络药理学  分子对接

Key words:  Fangji Huangqi Decoction  nephritic edema  network pharmacology  molecular docking

摘要:

[目的] 基于网络药理学探讨防己黄芪汤治疗肾性水肿的潜在作用机制，并通过分子对接技术进行验证。[方法] 运用中药系统药理学数据库（TCMSP）筛选防己黄芪汤所含有效化合物，分别运用Uniprot、Swiss target prediction数据库获取防己黄芪汤作用靶点，根据Gene Card和OMIM数据库获取肾性水肿相关靶点，与防己黄芪汤的潜在靶点取交集后得到“疾病－药物”靶基因，利用String软件构建蛋白互作网络，使用R4.0.0软件的ClusterProfiler和pathview生物包进行基因本体论（GO）、京都基因与基因组百科全书（KEGG）富集分析，最后运用Autodock Vina行分子对接对网络药理学结果进行验证。[结果] 防己黄芪汤与肾性水肿的交集基因共有39个。蛋白互作网络根据频数分析（P<0.05），防己黄芪汤治疗肾性水肿的机制可能与白细胞介素-6（IL-6）、肿瘤坏死因子（TNF）-α、血管内皮生长因子（VEGFA）、腺苷酸激酶同工酶1（ATK1）、白细胞介素-10（IL-10）等靶点有关。经KEGG富集分析（P<0.05），晚期糖基化终产物与晚期糖基化终产物受体（AGE-RAGE）信号通路、疟疾信号通路、TNF信号通路、流体剪切应力和动脉粥样硬化信号通路、低氧诱导因子-1（HIF-1）信号通路等可能为防己黄芪汤治疗肾性水肿的关键通路。分子对接验证结果显示山奈酚与TNF-α转化酶（TACE）抑制剂3EWJ和3E8R的配体结构相似，分子结合能分别为-9.3 KJ/moL和-9.5 KJ/moL，山奈酚与受体可自由结合。[结论] 防己黄芪汤主要成分槲皮素、山奈酚、异鼠李素等可能通过调控AGE-RAGE和TNF信号通路来发挥治疗肾性水肿的作用。

Abstract:

[Objective] To explore the potential mechanism of Fangji Huangqi Decoction in the treatment of nephritic edema by network pharmacology and verify it with molecular docking technology.[Methods] Based on the traditional Chinese medicine database system pharmacology (TCMSP) to screen out the effective targets of Fangji Huangqi Decoction. With the Uniprot, Swiss target prediction database for the studies of Fangji Huangqi Decoction targets, according to the Gene Card and OMIM database, we search potential access for nephritis edema. Then the disease-drug protein in intersection were upload for String for protein interaction network. The Go and KEGG enrichment analysis were performed with Cluster profile and Pathview biological package of R4.0.0 software. Finally, molecular docking was performed with Antocks Vina to verify the feasibility results.[Results] There were 39 genes of intersection between Fangji Huangqi Decoction and nephritic edema. According to the protein interaction network analysis, Fangji Huangqi Decoction may act on interleukin 6 (IL-6), tumor necrosis factor (TNF), vascular endothelial growth factor (VEGFA), adenylate kinase enzyme 1 (ATK1), interleukin 10 (IL-10) and other related proteins in the treatment of nephritic edema. The KEGG enrichment analysis found that the treatment of nephritic edema by Fangji Huangqi Decoction may be associated with AGE-RAGE signaling pathway, Malaria signaling pathway, TNF signaling pathway, Fluid shear stress and atherosclerosis signaling pathway and HIF-1 signaling pathway. The results showed that the ligand structure of kaempferol and TNF-α transferase (TACE) inhibitors 3EWJ and 3E8R were similar. The molecular binding energies of kaempferol were -9.3 (KJ/mol) and -9.5 (KJ/mol) respectively, and kaempferol could bind to the receptor freely.[Conclusion] Quercetin, kaempferol and isorhamnetin, the main components of Fangji Huangqi Decoction, may regulate TNF and AGE-RAGE signaling pathway to treat nephritic edema.