基于网络药理学和分子对接技术探讨糖网明目颗粒治疗糖尿病视网膜病变的作用机制

Mechanism of Tangwang Mingmu Granules in treating diabetic retinopathy based on network pharmacology and molecular docking

关键词:  糖网明目颗粒  糖尿病视网膜病变  网络药理学  分子对接  疾病-靶点网络

Key words:  Tangwang Mingmu Granule  diabetic retinopathy  network pharmacology  molecular docking  disease-target network

摘要:

[目的] 通过网络药理学和分子对接技术研究糖网明目颗粒治疗糖尿病视网膜病变（DR）的潜在分子机制，为糖网明目颗粒防治DR新药研发提供方向。[方法] 在中药系统药理分析平台（TCMSP）检索糖网明目颗粒组成药物的化学成分信息，通过PharmMapper服务器，Disgenet和GeneCards数据库建立活性成分靶点数据库和DR靶基因数据库，进行靶点匹配获取药物-疾病共同靶点。随后构建PPI网络图，并筛选核心靶点，构建中药-活性成分-核心靶点网络图。用R-4.1.1对药物-疾病共同靶点进行GO和KEGG富集分析。最后使用AutoDock软件进行分子对接分析，并用Pymol和Discovery Studio软件将结果可视化。在此基础上通过体外细胞实验对上述结果进行验证。[结果] 本文筛选得到糖网明目颗粒-DR共同靶点62个；GO富集分析确定了226个项目，KEGG通路富集筛选得到163条信号通路，主要有糖尿病并发症中的晚期糖基化产物（AGE）-晚期糖基化终末产物受体（RAGE）信号通路、肿瘤坏死因子（TNF）信号通路、FoxO信号通路等多种途径。分子对接结果显示糖网明目颗粒的有效成分木犀草素、表儿茶素及花生四烯酸等能与靶蛋白骨形态发生蛋白2（BMP2）、表皮生长因子受体（EGFR）和纤维连接蛋白1（FN1）等形成较为稳定的分子结合。在高糖诱导的人视网膜母瘤细胞Y79中，糖网明目颗粒能够抑制EGFR和丝裂原活化蛋白激酶（MAPK）14的蛋白表达。[结论] 本研究初步探讨了糖网明目颗粒治疗DR的作用机制，结果表明糖网明目颗粒治疗DR具有多成分，多靶点，多途径协同发挥药效的特点，为后续深入研发提供指导与部分依据。

Abstract:

[Objective] The potential molecular mechanism of Tangwang Mingmu Granules in the treatment of diabetic retinopathy (DR) was studied by network pharmacology and molecular docking technology,to provide an experimental basis for the development of new drugs of Tangwang Mingmu Granules for the prevention and treatment of DR.[Methods] The chemical composition information of the drugs comprising Tangwang Mingmu Granules was retrieved on Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform (TCMSP). The active component target database and DR target gene database were established via PharmMapper server,Disgenet and GeneCards databases,and target matching was performed to obtain the drug-disease common target. Subsequently,the PPI network diagram was constructed,and the core targets were screened,and the traditional Chinese medicine-active ingredient-core target network diagram was constructed. GO and KEGG enrichment analyses for drug-disease common targets were performed using R-4.1.1. Finally,molecular docking analysis was performed using Auto Dock software,and the results were visualized using Pymol and Discovery Studio software. On this basis,the above results were verified by in vitro cell experiments.[Results] In this study,62 common targets of Tangwang Mingmu Granules-DR were screened. The 226 items were identified by GO enrichment analysis,and 163 signaling pathways were identified by KEGG pathway enrichment screening,including AGE-RAGE signaling pathway,TNF signaling pathway,FoxO signaling pathway and other pathways in diabetic complications. Molecular docking results showed that the active components of Tangwang Mingmu Granules,such as luteolin,epicatechin and arachidonic acid,could form relatively stable molecular binding with target proteins,such as BMP2,EGFR and FN1. In human retinoblastoma cell Y79 induced by high glucose,Tangwang Mingmu Granules can inhibit the protein expression of EGFR and MAPK14.[Conclusion] In this study,the mechanism of Tangwang Mingmu Granules in the treatment of DR was preliminarily explored,and the results showed that Tangwang Mingmu Granules had the characteristics of multi-components,multi-targets,and multi-pathway synergy in the treatment of DR,which would provide guidance and part of the basis for further research and development.