基于网络药理学和分子对接探究色氨酸及其代谢物对阿尔茨海默病的作用机制

Exploring mechanism of tryptophan and its metabolites on Alzheimer’s disease based on network pharmacology and molecular docking technology

目的:采用网络药理学和分子对接技术探究色氨酸及其代谢物对神经变性疾病阿尔茨海默病(AD)的作用机制。方法:借助数据库及文献调研筛选色氨酸及其体内代谢物为研究对象,Swiss Target Prediction在线平台预测色氨酸及其代谢物作用靶点,通过GeneCards、OMIM、TTD数据库获取AD疾病靶点,利用Venny 2.1软件获取交集靶点。借助Cytoscape 3.9.1软件构建“目标化合物-靶点”网络图。使用String在线平台进行蛋白相互作用(PPI)分析,结合Cytoscape 3.9.1软件构建PPI网络图,通过度值、中介中心性、节点紧密度筛选关键靶点。采用DAVID数据库对交集靶点进行基因本体(GO)和京都基因与基因组百科全书(KEGG)通路富集分析。通过RCSB PDB和PubChem数据库获得靶点和化合物的结构,利用pymol软件和autodock vina软件进行分子对接。结果:筛选出色氨酸及其代谢物共11个目标化合物,包括邻氨基苯甲酸、犬尿酸、黄嘌呤酸、朱砂精酸、喹啉酸、色胺、血清素、褪黑素、N-甲酰犬尿氨酸、色氨酸、5-羟吲哚乙酸。筛选得到233个成分靶点基因,1824个疾病靶点基因以及80个交集基因,涉及作用于AD的GO分析475条,KEGG分析120条,涉及的关键靶点为MMP 9、NR3C1、PTGS 2、MAPK 1、EGFR等多个靶点,涉及多巴胺能突触、神经活性配体-受体相互作用、前列腺癌、cAMP信号通路、FOXO信号通路等通路。分子对接结果显示色氨酸及其代谢物与AD关键靶点结合活性较高且对接构象较稳定。结论:色氨酸及其代谢物通过多靶点、多通路发挥防治AD的作用。

Objective:This study was designed to explore the potential mechanism of tryptophan and its metabolites on Alzheimer's disease(AD)of neurodegenerative diseases based on network pharmacology and molecular docking technology.Methods:According to database screening and literature investigation,tryptophan and its metabolites were selected as research objects,and their possible action targets were screened by Swiss Target Prediction network platform,the targets related to AD were obtained through GeneCards,OMIM and TTD databases,and their intersection was screened by Venny 2.1 platform.“target compounds-targets”network diagram was formed by Cytoscape 3.9.1 software.String platform was chosen to analyze the Protein-protein interaction(PPI).Cytoscape 3.9.1 software as a tool to construct PPI network diagram,key targets were screened by the values of degree,closeness and betweenness,Gene ontology(GO)function and Kyoto encyclopedia of genes and genomes(KEGG)pathway enrichment analysis of intersection were performed by DAVID database.The structures of targets and compounds were obtained through RCSB PDB and PubChem databases,and molecular docking was performed using pymol software and autodock vina software.Results:The 11 target substances were selected,including N-formylkynurenine,melatonin,anthranilic acid,kynurenic acid,xanthurenic acid,cinnabarinic acid,quinolinic acid,tryptamine,serotonin,5-hydroxyindole acetic acid.Eighty intersection genes were screened.There were 475 GO analysis and 120 KEGG analysis related to AD.This study screened key target proteins,such as MMP9、NR3C1、PTGS2、MAPK1 and EGFR.The results also suggested that some main signaling pathways were involved into the pathogenesis of AD,including dopaminergic synapse,neuroactive ligand-receptor interaction,prostate cancer,cAMP signaling pathway and FOXO signaling pathway and so on.The results of molecular docking showed that tryptophan and its metabolites had high binding activity to AD key targets and stable docking conformation.Conclusion:Tryptophan and its metabolites play a role in the prevention and treatment of AD through multi-target and multi-pathway.