基于网络药理学和分子对接探究养肝益水颗粒治疗高血压肾病的作用机制

A study on the mechanism of the Yanggan Yishui granules in treating hypertensive nephropathy based on network pharmacology and molecular docking

目的:采用网络药理学方法探讨养肝益水颗粒治疗高血压肾病的作用机制,并通过分子对接技术进行验证。方法:从中药系统药理学数据库与分析平台(TCMSP)和UniProt平台中收集养肝益水颗粒组方的活性化合物和靶标。利用基因表达数据库(GEO)获得与人类相关的高血压肾病疾病靶点。以药物与疾病的交集靶点作为治疗靶点,通过STRING在线平台构建蛋白质-蛋白质相互作用网络,运用Cytoscape 3.9.1软件筛选出治疗的核心基因并进行富集分析及结果可视化。最后,采用PyMol软件完成分子对接验证。结果:共筛选出171个养肝益水颗粒生物活性化合物,282个药物靶点,715个高血压肾病疾病靶点,28个交集靶点。对蛋白质-蛋白质相互作用网络进行拓扑分析,得到27个相关基因。富集分析结果提示,养肝益水颗粒可能通过影响糖尿病并发症中的晚期糖基化终末产物(Advanced Glycation End-Product,AGE)-晚期糖基化终末产物受体(Advanced Glycation End Product Receptor,RAGE)信号通路、肿瘤坏死因子信号通路、流体剪切应力和动脉粥样硬化、缬氨酸、亮氨酸和异亮氨酸降解、蛋白质消化和吸收等,在高血压肾病的治疗中发挥作用,并绘制通路图。通过筛选得到5个核心基因和5个主要活性成分进行分子对接。结果表明,筛选得到的生物活性化合物与核心基因具有很强的结合能力。结论:本研究通过蛋白质-蛋白质相互作用、基因本体论(GO)功能富集分析、京都基因与基因组百科全书(KEGG)富集分析、分子对接、通路预测进行综合分析。养肝益水颗粒具有多组分、多靶点、多途径的复杂机制,其可能通过过氧化物酶体增殖物激活受体γ(Peroxisome Proliferator Activated Receptor Gamma,PPARG)干预转化生长因子-β(Transforming Growth Factor-β,TGF-β)达到减轻高血压肾损害的目的。相关临床研究也表明,养肝益水颗粒具有抗炎、减少尿蛋白的作用。本研究为养肝益水颗粒临床应用于高血压肾损伤提供了理论依据。

Objective:To study the mechanism of Yanggan Yishui granules(养肝益水颗粒)in treating hypertensive nephropathy by network pharmacology and and to verify it by molecular docking technology.Methods:Active compounds and targets of Yanggan Yishui granules were collected from the TCM System Pharmacology Database and Analysis Platform(TCMSP)and UniProt platform.Human relevant hypertensive nephropathy disease targets were obtained by using GEO database.The intersection target of drugs and diseases was taken as the therapeutic target.The protein-protein interaction network was constructed by String online platform.Cytoscape 3.9.1 software was used to select the core genes for treatment,and the enrichment analysis and results visualization were carried out.Finally,PyMol software was used to verify the molecular docking.Results:A total of 171 bioactive compounds,282 drug targets,715 targets of hypertensive nephropathy and 28 intersection targets of Yanggan Yishui granules were screened.The protein-protein interaction network was topologically analyzed and 27 related genes were obtained.The results of enrichment analysis suggested that Yanggan Yishui granules may play a role in the treatment of hypertensive-nephropathy by influencing AGE-RAGE signaling pathway,tumor necrosis factor signaling pathway,fluid shear stress and atherosclerosis,degradation of valine,leucine and isoleucine,protein digestion and absorption in diabetic complications,and mapping the pathway.Five core genes and five main active components were selected for molecular docking.The results showed that the selected bioactive compounds had strong binding ability to the core genes.Conclusion:In this paper,PPI protein interaction,GO enrichment analysis,KEGG enrichment analysis,molecular docking and pathway prediction are used for comprehensive analysis.Yanggan Yishui granules has a complex mechanism of multi-component,multi-target,and multi-pathway,which may reduce hypertensive renal damage by intervening TGF-βwith PPARG.Related clinical studies have also shown that Yanggan Yishui granules has anti-inflammatory and proteinolytic effects.In conclusion,this study provides a theoretical basis for the clinical application of Yanggan Yishui granules in hypertensive kidney injury.