钩藤-牛膝药对治疗肾血管性高血压的潜在分子机制

Potential mechanisms of RUCU-ABR drug pair in the treatment of renovascular hypertension

目的应用网络药理学及分子对接技术探讨钩藤-牛膝药对活性成分治疗肾血管性高血压的潜在机制。方法通过检索中药系统药理学数据库(TCMSP),获取钩藤、牛膝的化学成分和潜在靶标。检索人类孟德尔遗传数据库(OMIM)、人类基因蛋白质组数据库(GeneCards)、药物信息数据库(DrugBank)以及人类疾病基因数据库(DisGeNET),获取肾血管性高血压相关靶点。使用Cytoscape3.8.2软件构建"成分-靶标-疾病"网络。利用STRING平台绘制关键靶点蛋白互作网络。针对关键靶标,开展基因本体(GO)数据库基因蛋白富集分析、京都基因与基因组百科全书(KEGG)信号通路富集分析。使用AutoDock4.2.3软件对钩藤-牛膝药对的8个活性成分和6个核心靶点进行分子对接验证。结果检索得到钩藤-牛膝药对中有效成分54个、潜在靶标199个,其中涉及肾血管性高血压的关键靶标38个。蛋白质相互作用(PPI)网络图分析发现,IL-6、血管内皮生长因子A(VEGFA)、基质金属蛋白酶9(MMP9)、一氧化氮合酶3(NOS3)、前列腺素内过氧化物合酶2(PTGS2)、FOS、血红素加氧酶1(HMOX1)可能是钩藤-牛膝药对治疗肾血管性高血压的核心靶点。GO富集分析结果:涉及内质网腔、含胶原细胞外基质等细胞组分,血红素结合、细胞因子受体结合等分子功能,以及氧化应激、炎症反应调节等生物过程。KEGG富集分析结果:主要涉及糖基化终末产物、肿瘤坏死因子、低氧诱导因子等信号通路。分子对接显示:黄连碱、钩藤碱等活性成分与NOS3的结合能绝对值较高。结论在钩藤-牛膝药对治疗肾血管性高血压的活性成分中,黄连碱、钩藤碱均与NOS3结合较好,NOS3可能是钩藤-牛膝药对治疗肾血管性高血压的潜在靶标。

Objective To explore the potential mechanism of a drug pair of Ramulus Uncariae Cum Uncis(RUCU)-Achyranthis Bidentatae Radix(ABR)in the treatment of renovascular hypertension through the network pharmacology and molecular docking technology.Methods The chemical components and potential targets of RUCU and ABR were obtained by searching the database of Traditional Chinese Medicine Systems Pharmacology(TCMSP).By retrieving the Online Mendelian Inheritance in Man(OMIM)database,human gene proteome database(GeneCards),drug information database(DrugBank),and human disease gene database(DisGeNET),renovascular hypertension-related targets were obtained.By means of the Cytoscape 3.8.2 software,a"component-target-disease"network was established.The STRING platform was used to draw the interaction network of the key target proteins.For the key targets,the gene ontology(GO)database was used for gene protein enrichment analysis,while the Kyoto Encyclopedia of Genes and Genomes(KEGG)was used for signal pathway enrichment analysis.The AutoDock 4.2.3 software was used to verify the molecular docking of 8 active components and 6 core targets of the RUCU-ABR drug pair.Results Through the retrieving,54 active ingredients and 199 potential targets were obtained from the RUCU-ABR drug pair,among which 38 key targets were related to renovascular hypertension.Analysis of the protein-protein interaction network(PPI)showed that IL-6,vascular endothelial growth factor A(VEGFA),matrix metalloproteinase 9(MMP9),nitric-oxide synthase 3(NOS3),prostaglandin-endoperoxide synthase 2(PTGS2),FOS,and heme oxygenase 1(HMOX1)might be core targets for treatment of renal vascular hypertension with RUCU-ABR drug pair.GO enrichment analysis disclosed cell components(such as endoplasmic reticulum cavity and collagen containing extracellular matrix),molecular functions(such as heme binding and cytokine receptor binding),and biological processes(such as oxidative stress and inflammatory response regulation).KEGG enrichment analysis showed signaling pathways(such as advanced glycation end products,tumor necrosis factor,and hypoxia-inducible factor).Molecular docking found that the absolute value of binding energy of active ingredients such as coptisine and uncarine with NOS3 was relatively high.Conclusion Among the active ingredients of RUCU-ABR drug pair for treatment of renal vascular hypertension,coptisine and uncarine could all combine well with NOS3.NOS3 may be the potential target of RUCU-ABR drug pair in treating renal vascular hypertension.