摘要
目的基于网络药理学与分子对接技术探讨三七总皂苷治疗糖尿病足的潜在靶点及作用机制。方法通过本草组鉴数据库、PharmMapper平台收集三七总皂苷主要活性成分及其相关靶点,在GeneCards数据库和比较毒理基因组学数据库收集糖尿病足相关靶点,获得药物与疾病的共同靶点。将共同靶点导入STRING平台,构建蛋白质相互作用(PPI)网络,经拓扑分析确定核心靶点。用R软件对共同靶点进行基因本体论(GO)和京都百科全书基因和基因组(KEGG)富集分析。采用Cytoscape软件绘制成分—靶点—通路网络,拓扑分析筛选PNS治疗糖尿病足的核心成分与核心靶点。采用AutoDock Vina软件对核心靶点和药物进行分子对接模拟,验证网络药理学预测的结果。结果PNS的主要入血活性成分为三七皂苷R1、人参皂苷Rb1、人参皂苷Rd、人参皂苷Re和人参皂苷Rg1。共筛选得到PNS和糖尿病足的共同靶点56个,涉及多个生物过程和多条通路,包括伤口修复、对脂多糖的反应、对氧化应激的反应、平滑肌细胞增殖的调节、细胞间黏附的调节、神经元死亡调节、上皮细胞迁移等过程和糖尿病并发症AGE-RAGE信号通路、脂质与动脉粥样硬化、Toll样受体信号通路、PI3K-AKT信号通路、HIF-1信号通路等。PPI网络和成分—靶点—通路网络拓扑分析筛选出4个核心靶点丝氨酸/苏氨酸激酶1(AKT1)、基质金属蛋白酶9(MMP9)、表皮生长因子受体(EGFR)和转化蛋白p21(HRAS),分子对接验证显示,4个靶点与PNS活性成分结合能均能稳定结合(结合能<-5 kcal/mol)。结论PNS活性成分通过靶向调控AKT1、MMP9、EGFR、HRAS等关键靶点,发挥促进上皮细胞增殖、调节炎症反应、抗氧化反应、促血管生成、抗神经元细胞死亡等作用,从而达到治疗糖尿病足的效果,其核心通路主要涉及糖尿病并发症AGE-RAGE信号通路、脂质与动脉粥样硬化通路、PI3K-AKT信号通路、Toll样受体信号通路、MAPK信号通路、HIF-1信号通路、TNF信号通路等。
Objective To explore the potential therapeutic targets and mechanisms of action of panax notoginseng saponins(PNS)in the treatment of diabetic foot based on network pharmacology and molecular docking techniques.Methods The active ingredients and their related targets of PNS were collected through the HERB database and Pharm⁃Mapper platform,and the targets related to diabetic foot were collected in the GeneCards database and comparative toxi⁃cogenomics database to obtain the common targets of drugs and diseases.The common targets were imported into the STRING platform to construct a protein-protein interaction(PPI)network,and the core targets were identified by topologi⁃cal analysis.Gene ontology(GO)and Kyoto Encyclopedia of Genes and Genomes(KEGG)enrichment analyses were per⁃formed on the common targets using R software.Component-target-pathway networks were mapped using Cytoscape soft⁃ware,and topological analysis was performed to screen the core ingredients and core targets of PNS for the treatment of dia⁃betic foot.Molecular docking simulations of the core targets and components were performed using AutoDock Vina software to validate the network pharmacological predictions.Results The main active ingredients of PNS were notoginsenoside R1,ginsenoside Rb1,ginsenoside Rd,ginsenoside Re and ginsenoside Rg1.Fifty-six common targets of PNS and diabet⁃ic foot were screened out,involving multiple biological processes and pathways,including wound repair,response to lipo⁃polysaccharide,response to oxidative stress,regulation of smooth muscle cell proliferation,regulation of intercellular ad⁃hesion,regulation of neuronal death,and regulation of epithelial cell death,and diabetes complications AGE-RAGE sig⁃naling pathway,lipid and atherosclerosis pathway,Toll-like receptor signaling pathway,PI3K-AKT signaling pathway,and HIF-1 signaling pathway,etc.Four core targets,AKT1,MMP9,EGFR and HRAS,were screened out by PPI net⁃work and component-target-pathway network topology analysis,and molecular docking validation showed that all four tar⁃gets were able to bind stably(binding energy<-5 kcal/mol)to the PNS active components.Conclusions The active in⁃gredients of PNS play the role of promoting epithelial cell proliferation,regulating inflammatory response,antioxidant re⁃sponse,pro-angiogenesis and anti-neuronal cell death through targeting and regulating key targets such as AKT1,MMP9,EGFR and HRAS,so as to achieve the effect of treating diabetic foot.The core pathways mainly involve diabetic complica⁃tions AGE-RAGE signaling pathway,lipid and atherosclerosis pathway,PI3K-AKT signaling pathway,Toll-like receptor signaling pathway,MAPK signaling pathway,HIF-1 signaling pathway,and TNF signaling pathway,etc.
作者
李元超
王佳荣
朱虹颖
王建波
LI Yuanchao;WANG Jiarong;ZHU Hongying;WANG Jianbo(Department of Interventional Radiology,Shanghai Sixth People's Hospital Affiliated to Shanghai Jiaotong University School of Medicine,Shanghai 200233,China)
出处
《山东医药》
CAS
2023年第8期16-20,共5页
Shandong Medical Journal
基金
国家自然科学基金项目(82274252)。
关键词
三七总皂苷
糖尿病足
网络药理学
分子对接
panax notoginseng saponins
diabetic foot
network pharmacology
molecular docking
