基于网络药理学和分子对接探究槲皮素治疗阿尔茨海默病的作用机制

Explore the Mechanism of Quercetin in the Treatment of Alzheimer's Disease by Network Pharmacology and Molecular Docking

目的:基于网络药理学和分子对技术探究槲皮素治疗阿尔茨海默病(Alzheimer's disease,AD)的作用机制。方法:利用中药系统药理学数据库与分析平台(Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform,TCMSP)、PubChem数据库和Swiss Target Prediction平台预测槲皮素潜在靶点,利用Disgenet数据库获得AD的潜在靶点。通过维恩图对槲皮素潜在靶点和AD潜在靶点取交集得到共同靶点,将共同靶点导入DAVID数据库,以P<0.05进行筛选,进行基因本体(gene ontology,GO)分析和京都基因与基因百科全书(Kyoto Encyclopedia of Genes and Genomes,KEGG)通路富集分析。运用STRING数据库构建蛋白质-蛋白质相互作用(protein-protein interaction,PPI)网络,通过Cytoscape 3.6.0软件的centiscape 2.2插件对PPI网络进行分析,得到槲皮素治疗阿尔茨海默病的关键靶点。将关键靶点按照Degree从大到小排序取前5为核心靶点,使用SailVina final软件对筛选出的核心靶点进行分子对接。结果:三个数据库得到槲皮素潜在靶点有319个、阿尔茨海默病潜在靶点有673个,交集靶点有92个,筛选出的关键靶点有23个,GO分析中生物过程主要有基因表达正调控、细胞凋亡过程的正调控、对外源性刺激的反应、细胞凋亡过程的负调控等。KEGG通路分析主要富集在IL-17、HIF-1、FoxO、TNF、PI3K-Akt、MAPK等信号通路。槲皮素与核心靶点IL-6、AKT、TP53、TNF、IL-1β分子对接的平均对接亲和力为-7.92 kcal·mol^(-1),结合活性较好。结论:利用网络药理学和分子对接技术预测了槲皮素治疗AD的潜在靶点及信号通路,为后续实验研究提供理论基础。

Objective:To investigate the mechanism of quercetin in the treatment of Alzheimer's disease based on network pharmacology and molecular docking.Methods:Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform,PubChem database and Swiss Target Prediction platform were used to predict potential targets of quercetin.Potential targets for Alzheimer's disease were obtained through the Disgenet database.Common targets were obtained by intersection of potential quercetin targets and potential Alzheimer's disease targets through Venn diagram.The common targets were imported into DAVID database for screening at P<0.05,and gene ontology(GO)analysis and Kyoto Encyclopedia of Genes and Genomes(KEGG)pathway enrichment analysis were performed.The protein-protein interaction(PPI)network was constructed utilizing STRING database.The centiscape 2.2 plug-in of Cytoscape 3.6.0 software was used to analyze the PPI network,and the key target of quercetin in the treatment of Alzheimer’s disease was obtained.The top 5 key targets will be selected as the core targets in order of degree from largest to smallest,and the selected core targets will be subjected to molecular docking with SailVina final software.Results:There were 319 potential targets of quercetin in the three databases,673 potential targets of Alzheimer's disease,92 intersection targets,and 23 key targets screened out.The biological processes in GO analysis mainly included positive regulation of gene expression,positive regulation of apoptosis,response to exogenous stimuli,and negative regulation of apoptosis.KEGG pathway analysis mainly concentrated in IL-17,HIF-1,FoxO,TNF,PI3K-Akt,MAPK signaling pathway and so on.The average docking affinity between quercetin and core target molecules was-7.92 kcal·mol^(-1).Quercetin has good binding activity with the core targets IL-6,AKT,TP53,TNF and IL-1β.Conclusion:The potential targets and signaling pathways of quercetin in the treatment of AD have been found by network pharmacology and molecular docking techniques,which provided theoretical basis for subsequent experimental studies.