甘草抗慢性呼吸系统疾病糖皮质激素耐药的网络药理学及分子对接研究

Network pharmacology and molecular docking study of licorice against glucocorticoids resistance in chronic respiratory diseases

以慢性阻塞性肺病(COPD)和支气管哮喘为示范,运用网络药理学和分子对接技术探究甘草抗糖皮质激素耐药的分子机制.通过TCMSP数据库检索甘草潜在有效成分和作用靶点,利用Uniprot数据库查询靶点对应基因,并利用Cytoscape3.9.1软件构建成分-靶点(基因)可视化网络.应用GeneCards、OMIM、NCBI-gene数据库检索糖皮质激素耐药靶点或不敏感靶点(glucocorticoid resistance target or insensitive target,GROI)、COPD靶点、哮喘靶点,在String数据库构建交集靶点的蛋白互作(PPI)网络,并通过Centiscape2.2计算得到核心靶点,利用Metascape数据库对核心靶点进行富集分析,采用分子对接技术对潜在有效成分和目标蛋白进行验证.共获得甘草成分87个及其对应靶点230个、GROI靶点基因3992个、COPD靶点基因791个、哮喘作用靶点基因1988个.核心靶点基因为IL6、TP53、VEGFA、MMP9和JUN等.甘草发挥作用的潜在有效成分为槲皮素、山奈酚、柚皮素和芒柄花素等.GO分析结果表明,甘草抗糖皮质激素耐药机制主要涉及氧化应激、生长因子刺激、细胞增殖、迁移、死亡、分化、DNA结合转录因子活性的调节等生物学过程.KEGG通路富集分析表明,甘草通过调节脂质及动脉粥样硬化通路、MAPK信号通路、HIF-1信号通路和FoxO信号通路等发挥增效减毒作用.分子对接技术验证了槲皮素、山奈酚、柚皮素和芒柄花素与核心靶点蛋白IL6、TP53、VEGFA、MMP9和JUN具有较高的亲和力.

Using chronic obstructive pulmonary disease(COPD)and bronchial asthma as examples,network pharmacology and molecular docking techniques were used to explore the molecular mechanism of anti-glucocorticoid resistance in licorice.The potential active components and targets of licorice were retrieved from TCMSP database,and the corresponding genes of the targets were searched from Uniprot database.Cytoscape3.9.1 software was used to construct the component-target(gene)visu-alization network.Glucocorticoid resistance targets or insensitive targets(GROI),COPD targets,asthma targets were searched by GeneCards,OMIM,and NCBI-gene database.The PPI network of intersection targets was constructed in String database,and the core targets were calculated by Centiscape2.2.The core targets were enriched and analyzed by Metascape database.Fi-nally,the potential active components and target proteins were verified by molecular docking technology.A total of 87 licorice ingredients and 230 corresponding target sites,3992 target genes of GROI,791 target genes of COPD,and 1988 target genes of asthma were obtained.Core target genes included IL6,TP53,VEGFA,MMP9 and JUN,et al.The potential active compo-nents of licorice included quercetin,kaempferol,naringenin and formononetin,et al.GO analysis showed that the mechanism of anti-glucocorticoid resistance in licorice mainly involved oxidative stress,growth factor stimulation,cell proliferation,mi-gration,death,differentiation,regulation of DNA-binding transcription factor activity and other biological processes.The en-richment of KEGG pathway indicated that licorice played a synergistic and attenuating role by regulating lipid and atherosclero-sis pathways,MAPK signaling pathway,HIF-1 signaling pathway and FoxO signaling pathway.The high affinity of quercetin,kaempferol,naringenin and formononetin to IL6,TP53,VEGFA,MMP9 and JUN was verified by molecular docking technology.