基于网络药理学探讨交泰丸治疗失眠的作用机制

Mechanism of relieves insomnia effect of Jiaotai pills based on network pharmacology

目的通过网络药理学和分子对接技术对交泰丸治疗失眠的作用机制进行研究。方法交泰丸活性成分由中药系统药理学数据库与分析平台(Traditional Chinese Medicine Systems Pharmacology Database andAnalysis Platform,TCMSP)、中医药整合药理学研究平台(Integrative Pharmacology-based Research Platform of Traditional Chinese Medicine,TCMIP)整合获得,SwissTargetPrediction数据库预测作用靶点,整合DisGeNET、DrugBank疾病基因数据库中失眠的靶点基因。采用Venny 2.1在线软件作图工具平台,获取活性成分与失眠靶点的交集靶,Cytoscape 3.9.1作图软件构建交泰丸活性成分的交集靶点网络,分析得到交泰丸核心成分。蛋白互作网络、核心靶点由STRING12.0数据库获得,DAVID数据进行基因本体(gene ontology,GO)功能注释和京都基因与基因组百科全书(Kyoto Encyclopedia of Genes and Genomes,KEGG)通路富集分析,采用AutoDockTools1.5.7 Pymol软件对关键靶点与成分进行分子对接、可视化处理。结果筛选得到交泰丸中治疗失眠的5个核心成分依次为小檗碱、柠檬苦素、黄柏酮、N-反式阿魏酰酪胺、黄藤素,筛选出5-羟色胺(5-hydroxy tryptamine,5-HT)转运体(solute carrier family 6 member,SLC6A4)、多巴胺受体(dopamine receptor D2,DRD2)、烟碱乙酰胆碱受体(cholinergic receptor nicotinic alpha 4 subunit,CHRNA4)、肿瘤坏死因子(tumor necrosis factor,TNF)、前列腺素内过氧化物合酶(prostaglandin-endoperoxide synthase 2,PTGS2)等核心靶点。交泰丸治疗失眠的信号通路主要富集于调节5-HT能突触、多巴胺能突触等。分子对接显示核心成分小檗碱、柠檬苦素、黄柏酮等与核心靶点SLC6A4、DRD2、CHRNA4、TNF、PTGS2等对接程度良好。结论交泰丸中小檗碱、柠檬苦酸、黄柏酮等成分通过影响SLC6A4、DRD2、TNF、CHRNA4、PTGS2等蛋白的表达,多作用机制治疗失眠。

Objective To explore the potential mechanism of the relieves insomnia effect of Jiaotai pills by virtue of network pharmacology and molecular docking.Methods The active ingredients of Jiaotai pills are obtained by Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform(TCMSP),Integrative Pharmacology-based Research Platform of Traditional Chinese Medicine(TCMIP).Related targets of Jiaotai pills were predicted by SwissTargetPrediction.The potential targets associated with insomnia were retrieved from DisGeNET,DrugBank.Venny 2.1 was employed to identify the common targets shared by active components,insomnia,and core nodes,and the key components and key targets were screened by further topological analysis.The key components and key targets were analyzed by the network analysis plug-in of Cytoscape 3.9.1 and the core components were screened out.The protein-protein interaction network and the core targets were built by STRING 12.0.Gene ontology(GO)functional annotation and Kyoto Encyclopedia of Genes and Genomes(KEGG)pathway enrichment were performed in DAVID.AutoDockTools1.5.7 was used for the molecular docking between the key targets and the corresponding key components.Apply Pymol was used to visualize the results.Results A total of 5 active components of Jiaotai pills were screened,including Berberine,Limonin,Obacunone,Moupinamide,Palmatine,and core targets such as solute carrier family 6 member(SLC6A4),dopamine receptor D2(DRD2),cholinergic receptor nicotinic alpha 4 subunit(CHRNA4),tumor necrosis factor(TNF),and prostaglandin-endoperoxide synthase 2(PTGS2)were screened.The signaling pathways of Jiaotai pills for insomnia mainly concentrated in regulating 5-hydroxytryptaminergic synapses and dopamine synapses.Molecular docking showed that core components Berberine,Limonin,and Obacunone and core targets SLC6A4,DRD2,CHRNA4,TNF,and PTGS2 and so on were well docked.Conclusion Berlambine,Llimonin,Obacunone in Jiaotai pills through multiple mechanisms to treat insomnia by affecting the expression of SLC6A4,DRD2,TNF,CHRNA4,and PTGS2.