基于网络药理学和分子对接技术探讨知柏地黄丸治疗特发性中枢性性早熟的机制

Mechanism of Zhibai Dihuang Pills in the Treatment of Idiopathic Central Precocious Puberty Based on Network Pharmacology and Molecular Docking Technology

目的:通过网络药理学和分子对接技术探讨知柏地黄丸治疗特发性中枢性性早熟(ICPP)的作用机制。方法:基于中药系统药理学数据库与分析平台(TCMSP)和文献研究挖掘知柏地黄丸中各个药物的活性成分,并利用TCMSP数据库预测活性成分作用靶点,通过全球蛋白质资源(UniProt)数据库对靶点蛋白进行校正。在GeneCards、在线孟德尔遗传(OMIM)、DisGeNET数据库中获得ICPP的疾病靶点。取药物靶点和疾病靶点的交集靶点并制作韦恩图,运用Cytoscape 3.9.1软件制作“中药-活性成分-靶点”网络并进行网络拓扑分析获取中药核心成分,利用STRING数据库构建蛋白互作网络并导入Cytoscape 3.9.1软件中筛选出核心靶点。利用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)分析;利用AutoDockTools和AutoDock Vina脚本将得到的核心成分和核心靶点进行分子对接。结果:筛选得到知柏地黄丸复方中活性成分114个,相关靶点233个,ICPP疾病靶点1628个,交集靶点111个。复方核心成分包括槲皮素、山奈酚、β-谷甾醇、脱水淫羊藿素、豆甾醇等22个,核心靶点包括AKT1、FOS、ESR1、IL6、EGFR等14个。GO分析结果显示,交集靶点与基因表达的正向调节、DNA诱导转录的正向调节、RNA聚合酶2启动子转录正调节、突触后膜的组成、蛋白激酶结合等相关,KEGG分析结果主要涉及到AGE-RAGE信号通路、癌症通路、内分泌抵抗、细胞衰老等信号通路。分子对接结果显示,核心成分与靶点具有较好的结合活性。结论:知柏地黄丸治疗ICPP具有多成分、多靶点、多通路的特点,为进一步研究知柏地黄丸治疗ICPP的作用机制奠定了基础。

Objective:To explore the mechanism of Zhibai Dihuang pills in the treatment of idiopathic central precocious puberty(ICPP)based on network pharmacology and molecular docking technology.Methods:Based on literature research and retrieval of Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform(TCMSP),the active components of Zhibai Dihuang pills were obtained.TCMSP database was used to predict the target of active components,and the target protein was calibrated by the UniProt database.GeneCards,Online Mendelian Inheritance in Man(OMIM)and DisGeNET databases were used to obtain ICPP related target genes.Intersection targets of drug targets and disease targets were obtained to make Venn diagram.Cytoscape 3.9.1 was used to construct the“drug-active components-targets”network and perform topological analysis to obtain core components of traditional Chinese medicine.STRING database was used to construct the protein-protein interaction network and screen out the key targets.Intersection targets were analyzed by gene ontology(GO)and Kyoto encyclopedia of genes and genomes(KEGG)by using DAVID database.AutoDockTools and AutoDock Vina scripts were used to obtained core components and core targets for molecular docking.Results:A total of 114 active components of Zhibai Dihuang pills and 233 related potential targets were screened out,with 1,628 ICPP related target genes and 111 intersection targets.The 22 core components mainly included quercetin,kaempferol,β-sitosterol,icariin and stigasterol,and the 14 core targets mainly included AKT1,FOS,ESR1,IL6 and EGFR.GO analysis results showed that intersection targets were associated with positive regulation of gene expression,positive regulation of DNA-induced transcription,positive regulation of RNA polymerase 2 promoter transcription,postsynaptic membrane composition and protein kinase binding.KEGG analysis mainly involved signaling pathways such as advanced glycation end products-receptor of advanced glycation end products(AGE-RAGE)signaling pathway,cancer pathway,endocrine resistance,and cellular senescence.Molecular docking results showed that the core components had good binding activity to the targets.Conclusion:Zhibai Dihuang pills has multi-component,multi-target and multi-pathway characteristics in the treatment of ICPP,which lays foundation for further research on the mechanism of Zhibai Dihuang pills in the treatment of ICPP.