【摘要】 目的 探究养阴天香丹对冠心病西北燥证的药效物质基础。方法 通过TCMSP、PubChem、Herb数据库检索养阴天香丹主要成分,采用多组学整合分析策略系统解析药物作用机制。首先基于GeneCards和OMIM疾病数据库,采用“coronary heart disease”为关键词检索疾病相关靶点基因,并与药物活性成分作用靶点取Venn交集。随后运用Cytoscape 3.10.0构建多层级网络拓扑图,依据degree、betweenness等拓扑参数筛选关键活性成分。进一步通过STRING 11.5平台构建蛋白质互作网络(PPI),设置置信度阈值> 0.9,采用MCODE算法识别核心靶点模块。对关键靶点群进行功能注释分析,借助DAVID 6.8完成基因本体(GO)功能富集(包括生物过程、分子功能和细胞组分)及京都基因和基因组数据库(KEGG)通路分析。最终对筛选获得的核心成分-靶点对进行分子对接验证,采用Autodock Vina计算结合自由能,评估潜在相互作用强度。结果 检索到养阴天香丹5味主要成分,80种入血成分的靶点1 211个,冠心病靶点4 669个,药物与疾病交集靶点182个,关键成分为槲皮素、木犀草素、豆甾醇、丹参酮ⅡA、黄芩素,核心靶点为肿瘤坏死因子(TNF)、蛋白激酶B1(Akt1)、白细胞介素-6(IL-6)、白细胞介素-1β(IL-1β)、前列腺素内过氧化物合酶2(PTGS2)等;KEGG通路富集分析结果显示,养阴天香丹对冠心病西北燥证的作用机制可能与以下通路有关:晚期糖基化终产物-晚期糖基化终产物受体(AGE-RAGE)、白细胞介素-17(IL-17)、TNF、缺氧诱导因子-1(HIF-1)、磷脂酰肌醇3-激酶-蛋白激酶B通路(PI3K-Akt)信号通路等;分子对接结果显示,所有组合的对接结合能≤-6 kcal/mol,表明化合物与蛋白两者之间存在高亲和力结合。由分子动力学MD模拟结果可知,药物主要活性成分与核心靶点结合自由能小、亲和力高、体系稳定,与分子对接结果一致。结论 养阴天香丹中槲皮素、木犀草素、豆甾醇、丹参酮ⅡA、黄芩素等成分可能为治疗冠心病西北燥证药效物质基础,核心靶点是TNF、IL-6、Akt1、IL-1β、PTGS2等。养阴天香丹可能主要通过PI3K-Akt、HIF-1、IL-17、AGE-RAGE、TNF信号通路等参与冠心病西北燥证的治疗。更多还原

【Abstract】 Objective:To explore the pharmacodynamic material basis of Yangyin Tianxiang Pills in the treatment of coronary heart disease(CHD)with Northwest Dryness Syndrome. Methods:The main components of Yangyin Tianxiang Pills were retrieved from TCMSP,PubChem and Herb databases. A multi-omics integrated analysis strategy was adopted to systematically analyze the mechanism of drug action. First,based on GeneCards and OMIM disease databases,disease-related target genes were retrieved with the keyword “coronary heart disease”,and the Venn intersection was obtained with the targets of active components of the drug. Then,Cytoscape 3.10.0 was used to construct a multi-level network topological graph,and key active components were screened according to topological parameters such as degree and betweenness. Furthermore,the STRING 11.5 platform was used to construct a protein-protein interaction(PPI)network with the confidence threshold set at > 0.9,and the MCODE algorithm was adopted to identify core target modules. Functional annotation analysis was performed on the key target groups,and GO functional enrichment(including biological process,molecular function and cellular component)and KEGG pathway analysis were completed with DAVID 6.8. Finally,molecular docking verification was carried out on the screened core component-target pairs,and AutoDock Vina was used to calculate the binding free energy to evaluate the potential interaction intensity. Results:A total of 5 main components of Yangyin Tianxiang Pills were retrieved,with 1 211 targets of 80 blood-entry components,4 669 targets of CHD,and 182 intersection targets between the drug and the disease. The key components were quercetin,luteolin,stigmasterol,tanshinone ⅡA and baicalein,and the core targets were TNF,Akt1,IL-6,IL-1β,PTGS2,etc. KEGG pathway enrichment analysis showed that the mechanism of Yangyin Tianxiang Pills in treating CHD with Northwest Dryness Syndrome might be related to the following pathways:AGE-RAGE,IL-17,TNF,HIF-1 and PI3K-Akt signaling pathways. Molecular docking results showed that the docking binding energy of all combinations was ≤-6 kcal/mol,indicating that there was a high-affinity binding between compounds and proteins. Molecular dynamics(MD)simulation results showed that the main active components of the drug had low binding free energy,high affinity and stable system with the core targets,which were consistent with the molecular docking results. Conclusion:Components such as quercetin,luteolin,stigmasterol,tanshinone ⅡA and baicalein in Yangyin Tianxiang Pills may be the pharmacodynamic material basis for the treatment of CHD with Northwest Dryness Syndrome. The core targets are TNF,IL-6,Akt1,IL-1β,PTGS2,etc. Yangyin Tianxiang Pills may be involved in the treatment of CHD with Northwest Dryness Syndrome mainly through PI3K-Akt,HIF-1,IL-17,AGE-RAGE and TNF signaling pathways.更多还原