基于网络药理学及分子对接探讨补元汤干预慢性阻塞性肺疾病小气道功能障碍的作用机制

Mechanism of Buyuan Decoction in Intervening the Small Airway Dysfunction of Chronic Obstructive Pulmonary Disease Based on Network Pharmacology and Molecular Docking

目的:运用网络药理学及分子对接方法,探讨补元汤干预慢性阻塞性肺疾病(COPD)小气道功能障碍的作用机制。方法:通过中药系统药理学数据库与分析平台(TCMSP)筛选出补元汤活性成分和药物靶点;运用Cytoscape 3.9.1软件绘制补元汤活性成分-靶点相互关系网络图,并通过人类孟德尔遗传综合数据库和GeneCards等数据库查找COPD的靶点。通过Venny图筛选出补元汤与COPD的共同靶点,将筛选出的交集靶点导入STRING平台进行靶点蛋白质-蛋白质相互作用(PPI)分析、并借助Cytoscape 3.9.1软件实现可视化;利用Metascape网站进行基因本体(GO)生物信息学分析和京都基因与基因组百科全书(KEGG)通路富集分析,运用Autodock-vina 1.1.2、Mgltools 1.5.7和Pymol 2.4.0软件实现分子对接。结果:得到补元汤活性成分153个,作用靶点284个,COPD靶点1038个;补元汤与COPD的共同靶点49个,富集分析得到生物进程3879个,细胞学组分297个,分子功能414个,KEGG通路214条,补元汤治疗COPD的核心成分为山柰酚、槲皮素和谷甾醇,PPI结果显示补元汤作用于COPD的机制中白细胞介素6(IL-6)、基质金属蛋白酶9(MMP9)、肿瘤坏死因子(TNF)、蛋白激酶B(Akt)1、血管内皮生长因子A(VEGFA)和肿瘤蛋白p53(TP53)等靶点作用效果显著,其关键信号通路为晚期糖基化终末产物(AGE)-AGE受体(RAGE)和缺氧诱导因子-1(HIF-1)。结论:补元汤能够多成分、多靶点、多通路治疗COPD,通过山柰酚、槲皮素和谷甾醇等活性成分作用于IL-6、TNF、VEGFA、MMP9和Akt1等靶点,并通过AGE-RAGE信号通路和HIF-1信号通路,抑制细胞因子释放,减轻小气道过度免疫反应并消除炎症;防止小气道周围肺泡附着点被破坏,并促进血管生成,进而改善小气道功能,达到治疗COPD的效果,从而有效改善COPD患者的肺功能、运动耐力。

OBJECTIVE:To explore the mechanism of Buyuan Decoction on small airway dysfunction in chronic obstructive pulmonary disease(COPD)by using network pharmacology and molecular docking methods.METHODS:The active ingredients and drug targets of Buyuan Decoction were screened out through the TCMSP system pharmacological database and analysis platform(TCMSP).The network diagram of the relationship between the active ingredients and targets of Buyuan Decoction was drawn using Cytoscape 3.9.1,and the targets of COPD were found through the Mendelian genetic comprehensive database and GeneCards database.The common targets of Buyuan Decoction and COPD were screened out through Venny diagram,and the selected intersection targets were introduced into STRING platform for target protein-protein interaction(PPI)analysis,and visualization was realized with the help of Cytascape 3.9.1;The Metascape website is used for gene ontology(GO)bioinformatics analysis and Kyoto Encyclopedia of Genes and Genome(KEGG)pathway enrichment analysis,and Autodock-vina 1.1.2,Mgltools 1.5.7 and Pymol 2.4.0 are used to realize molecular docking.RESULTS:153 active components,284 targets of action and 1038 targets of COPD were obtained;There are 49 common targets of Buyuan Decoction and COPD.The enrichment analysis shows that there are 3879 biological processes,297 cytological components,414 molecular functions,and 214 KEGG pathways.The core components of Buyuan Decoction in treating COPD are kaempferol,quercetin,and sitosterol.PPI results show that the mechanism of Buyuan Decoction in treating COPD is interleukin 6(IL-6),matrix metalloproteinase 9(MMP9),tumor necrosis factor(TNF),and protein kinase B(Akt)1,vascular endothelial growth factor A(VEGFA)and tumor protein p53(TP53)have significant effects.The key signal pathways are advanced glycation end products(AGE)-AGE receptor(RAGE)and hypoxia inducible factor-1(HIF-1).CONCLUSIONS:Buyuan Decoction can treat COPD with multiple components,multiple targets and multiple pathways.It acts on targets such as IL-6,TNF,VEGFA,MMP9 and Aktl through active components such as kaempferol,quercetin and sitosterol,and inhibits the release of cytokines through AGE-RAGE signal pathway and HIF-I signal pathway,reduces the excessive immune response of small airways and eliminates inflammation,prevents the destruction of alveolar attachment points around small airways,and promotes angiogenesis,Then improve the small airway function,achieve the effect of treating COPD,and effectively improve the lung function and exercise endurance of COPD patients.