基于网络药理学及分子对接探讨润肝养心方治疗心脏神经症的分子机制

Molecular Mechanism of Rungan Yangxin Recipe in the Treatment of Cardiac Neurosis Based on Network Pharmacology and Molecular Docking

目的:基于网络药理学和分子对接方法探讨润肝养心方治疗心脏神经症(CN)的物质基础和作用机制。方法:通过中药系统药理学数据库与分析平台(TCMSP)、有机小分子生物活性数据库(PubChem)、Swiss Target Prediction数据库检索并筛选出润肝养心方(麦冬、酸枣仁、柏子仁、炒白芍、当归、五味子、茯苓、炙甘草)的药物活性成分及作用靶点,利用基因名片数据库(GeneCard)、在线人类孟德尔遗传数据库(OMIM)、DisGeNET数据库筛选CN疾病靶点,将药物和疾病靶点两者取交集后获得的共有靶点导入STRING数据库获得蛋白互作关系,应用Cytoscape 3.8.2软件构建蛋白质相互作用(PPI)网络;采用R语言ClusterProfiler程序包(3.18.0)对关键靶点进行基因本体(GO)和京都基因和基因组百科全书(KEGG)富集分析,并利用Cytoscape 3.8.2构建关键靶点-功能-通路图及关键靶点中药药理调控网络;采用AutoDock Tools 1.5.6进行分子对接研究。结果:润肝养心方筛选得到活性成分146个、作用靶点245个、CN及润肝养心方共有靶点如白细胞介素(IL)-1β、IL-6、肿瘤坏死因子(TNF)等38个。KEGG富集分析关键靶点主要被富集在神经活性配体-受体相互作用、晚期糖基化终末产物(AGE)-糖基化终末产物受体(RAGE)信号通路、脂质与动脉粥样硬化等信号通路,涉及对异源刺激的反应、管径调节、血管直径维持等生物过程。分子对接验证显示关键靶点与槲皮素、芍药苷、山柰酚的结合活性较好。结论:润肝养心方中主要活性成分可能通过调节IL-1β、IL-6、TNF等关键靶点基因及神经活性配体-受体相互作用、AGE-RAGE信号通路、脂质与动脉粥样硬化等多通路以发挥抗炎、调节神经递质水平等作用治疗CN。

Objective:To explore the material foundation and mechanism of Rungan Yangxin Recipe for the treatment of cardiac neurosis(CN)based on network pharmacology and molecular docking method.Methods:Traditional Chinese medicine(TCM)system pharmacology database(TCMSP),PubChem and Swiss Target prediction databases were used to search and screen the active components and action targets of Rungan Yangxin Recipe(ophiopogon japonicus,wild jujube kernel,cypress kernel,fried white peony,angelica sinensis,schisandra chinensis,poria cocos,roasted licorice).CN disease targets were screened using GeneCard database(GeneCard),Online Human Mendelian Genetic Database(OMIM)and DisGeNET database.The common targets were obtained after the intersection of drug,and disease targets were imported into STRING database to obtain the protein interaction relationship,and the protein interaction(PPI)network was constructed by Cytoscape 3.8.2 software.The gene ontology(GO)and the Kyoto Encyclopedia of Genes and Genomes(KEGG)were enriched and analyzed for key targets using the R ClusterProfiler package(3.18.0).The key target-function-pathway diagram and the key target pharmacology regulatory network of TCM were constructed by Cytoscape 3.8.2.Molecular docking was studied using AutoDock Tools 1.5.6.Results:A total of 146 active ingredients and 245 targets were obtained from Rungan Yangxin Recipe.CN and Rungan Yangxin Recipe shared 38 targets such as interleukin(IL)-1β,IL-6,tumor necrosis factor(TNF),etc.The key targets of KEGG enrichment analysis were mainly enriched in neuroactive ligand-receptor interaction,advanced glycation end products(AGE)-receptor for advanced glycation end products(RAGE)signaling pathways,lipid and atherosclerosis signaling pathways,involving biological processes such as response to xenobiotic stimulus,tube diameter regulation,and vessel diameter maintenance.Molecular docking test showed that the key target showed better binding activity with quercetin,paeoniflorin and kaempferol.Conclusion:The main active components of Rungan Yangxin Recipe may play anti-inflammatory and neurotransmitter role for treating cardiac neurosis by regulating key target genes such as IL-1β,IL-6,TNF,neuroactive ligand-receptor interaction,AGE-RAGE signaling pathway,lipid and atherosclerosis and other pathways.