小儿黄龙颗粒治疗注意缺陷多动障碍的网络药理学和分子对接研究

Xiaoer Huanglong Granules in the Treatment of Attention-Deficit Hyperactivity Disorder Based on Network Pharmacology and Molecular Docking

目的探讨基于网络药理学和分子对接技术的小儿黄龙颗粒治疗注意缺陷多动障碍(ADHD)的作用机制。方法计算机检索TCMSP数据库,筛选小儿黄龙颗粒的活性成分和对应靶点;检索DisGeNET,GeneCards,TTD,DrugBank,ADHDgene数据库,筛选ADHD相关靶点;利用Venny 2.1平台对小儿黄龙颗粒活性成分靶点与ADHD靶点取交集,获取共有靶点即为小儿黄龙颗粒治疗ADHD的潜在作用靶点。利用String数据库构建小儿黄龙颗粒治疗ADHD潜在作用靶点的蛋白互作网络(PPI),采用Cytoscape 3.8.0软件分析网络中的核心靶点。采用Metascape数据库进行GO富集分析和KEGG通路富集分析。采用AutoDockTools 1.5.6软件进行分子对接研究,以结合能<-4.25 kcal/mol为受体、配体间有一定的结合活性。结果共获得小儿黄龙颗粒的活性成分47种,靶点163个;ADHD靶点1115个;小儿黄龙颗粒治疗ADHD的潜在作用靶点55个。豆甾醇、7-甲氧基-2-甲基异黄酮、山柰酚、β-谷甾醇、木犀草素是小儿黄龙颗粒治疗ADHD的关键成分。PPI分析结果显示,白细胞介素6(IL-6)、蛋白激酶1(AKT1)、雌激素受体1(ESR1)、溶质载体家族6成员4(SLC6A4)、肾上腺素能受体β2(ADRβ2)和烟碱型胆碱受体α7(CHRNα7)6个靶点为小儿黄龙颗粒治疗ADHD的核心靶点。GO富集分析主要涉及突触传递、细胞对有机环状化合物及含氮化合物的反应等生物过程,突触后膜、树突、膜筏等细胞组分,神经递质受体活性、G蛋白偶联胺受体活性及单加氧酶活性等分子功能。KEGG通路富集分析主要涉及神经活性配体-受体相互作用、钙离子信号通路、磷脂酰肌醇-3-激酶/丝氨酸-苏氨酸蛋白激酶(PI3K/AKT)信号通路、环磷酸鸟苷/蛋白激酶G(cGMP/PKG)信号通路、胆碱能突触信号通路等。分子对接结果显示,核心靶点与其对应的关键成分结合能均小于-4.25 kcal/mol。结论小儿黄龙颗粒治疗ADHD具有多成分、多靶点、多通路的特点。

Objective To investigate the mechanism of Xiaoer Huanglong Granules in the treatment of attention-deficit hyperactivity disorder(ADHD)based on the network pharmacology and molecular docking technology.MethodsThe active components and corresponding targets of Xiaoer Huanglong Granules were screened by the TCMSP database,the related targets of ADHD were screened by the DisGeNET,GeneCards,TTD,DrugBank and ADHDgene databases.The targets of active components of Xiaoer Huanglong Granules and the targets of ADHD were intersected by the Venny 2.1 platform,and the common targets obtained were potential targets of Xiaoer Huanglong Granules in the treatment of ADHD.The protein-protein interaction(PPI)network of potential targets of Xiaoer Huanglong Granules in the treatment of ADHD was constructed by the String database,and the core targets in the network were analyzed by the Cytoscape 3.8.0 software.The GO enrichment analysis and KEGG pathway enrichment analysis were performed by the Metascape database.The molecular docking was performed by the AutoDockTools 1.5.6 software,and the binding energy<-4.25 kcal/mol indicated the receptor had a certain binding activity with the ligand.ResultsA total of47 active components of Xiaoer Huanglong Granules,163 targets of active components,1115 targets of ADHD and 55 potential targets of Xiaoer Huanglong Granules in the treatment of ADHD were obtained.Stigmasterol,7-methoxy-2-methyl isoflavone,kaempferol,β-sitosterol and luteolin were the key components of Xiaoer Huanglong Granules in the treatment of ADHD.The results of PPI network analysis showed that six targets including interleukin 6(IL-6),protein kinase 1(AKT1),estrogen receptor 1(ESR1),solute carrier family 6 member 4(SLC6A4),adrenoceptorβ2(ADRβ2)and cholinergic receptor,nicotinic,α7(CHRNα7)were the core targets of Xiaoer Huanglong Granules in the treatment of ADHD.GO enrichment analysis mainly involved biological processes such as synaptic transmission,cellular response to organic cyclic compounds and nitrogen compounds,cell components such as postsynaptic membrane,dendrites and membrane rafts,molecular functions such as neurotransmitter receptor activity,G protein-coupled amine receptor activity and monooxygenase activity.The KEGG pathway enrichment analysis mainly involved the neuroactive ligand-receptor interaction,calcium signal pathway,phosphatidylinositol-3-kinase/serine-threonine protein kinase(PI3K/AKT)signal pathway,cyclic guanosine monophosphate/protein kinase G(cGMP/PKG)signal pathway,cholinergic synaptic signal pathway and so on.The results of molecular docking showed that the binding energy of the core targets and their corresponding key components was less than-4.25 kcal/mol.ConclusionXiaoer Huanglong Granules in the treatment of ADHD has the characteristics of multi-component,multi-target and multi-pathway.