玉锁丹治疗糖尿病的网络药理学研究

Molecular Mechanism of Yusuodan in the Treatment of Diabetes Based on Network Pharmacology

目的运用网络药理学方法探讨玉锁丹(YSD)治疗糖尿病(DM)潜在活性成分和作用机制。方法根据TCMSP、TCMID、BATMAN-TCM平台及文献报道筛选YSD(茯苓、五倍子、龙骨)有效成分,并以SiwssTargetPrediction平台预测上述活性成分潜在靶点,同时利用Gencards、DisGeNET、DrugBank数据库挖掘DM相关靶点,将获取的活性成分靶点与疾病靶点交集得到YSD抗DM的预测靶点。利用STRING平台对预测靶点构建蛋白相互作用(PPI)网络并结合Mcode探索其蛋白质功能模块;通过Metascape数据库对预测靶点进行GO功能和KEGG通路富集分析,并以Cytoscape3.7.1软件构建"玉锁丹成分-糖尿病靶点-通路"网络,最后采用SiwssDock平台对YSD的化学成分与重要靶点进行分子对接验证。结果玉锁丹抗DM的核心活性成分为麦角胺、啤酒甾醇、杨梅素、猪苓酸C、25-羟基-3-表去氢土莫酸等,核心靶点为PTPN1、TNF、PIK3CA、PPARA、AGTR1等。分子对接验证显示G <-7 kcal/mol占总数71%,介于-6至-7占29%,即多数成分与靶点结合活性稳定。玉锁丹抗糖尿病的生物通路主要作用于Endocrine resistance、Insulin resistance、PI3K-Akt signaling pathway等,其功能主要调节激素水平及细胞内有机氮化合物等生命活动。结论玉锁丹抗糖尿病具有多成分-多靶点-多通路的作用特点,尤其与预防胰岛素抵抗,调节激素水平密切相关。

Objective To explore the potential active ingredients and related mechanism of Yusuodan(YSD) in treating Diabetes Mellitus(DM) with manners of network pharmacology. Methods Active ingredients of YSD were searched from the databases of TCMSP, TCMID and BATMAN-TCM at first. Then the potential targets were screened through SiwssTargetPrediction, while the DM related targets were searched from the databases of Gencards, DisGeNET, Drug Bank. Following, the intersecting targets of YSD and DM were made a PPI in the STRING and its protein function module were explored combining the Mcode. The GO function and KEGG pathways of screened targets were analyzed in Metascape database. Then the network of"components of YSD-targets of DM-pathways"were constructed in Cytoscape3.7.1. Finally, molecular docking between chemical constituents of YSD and key targets was conducted to make a verification.Results The key active ingredients in anti-DM of YSD were ergotamine, Cerevisterol, myricetin,Polyporenic acid C, 25-hydroxy-3-epidehydrotum-ulosic acid, 6 alph-a-Hydroxypolyporenic acid C. And its Critical targets were PTPN1, TNF, PIK3 CA, PPARA, AGTR1, etc. The result of molecular docking indicated that G <-7 kcal/mol accounted for 71% of the total and-6 < G <-7 kcal/mol accounted for 29%. This manifested that the combination with targets of most active ingredients was stable. The main pathways of YSD in treating DM were endocrine resistance,insulin resistance, PI3 K-Akt signaling pathway, etc. And regulating hormone levels and intracellular organonitrogen compounds were the main function. Conclusion The mechanism of YSD in treating DM was the combination of multicomponents, multi-targets and multi-pathways, especially related to preventing insulin resistance and regulating hormone levels.