基于网络药理学和分子对接探讨桂枝茯苓丸“异病同治”脑病的作用机制

[目的] 运用网络药理学与分子对接技术探究桂枝茯苓丸“异病同治”治疗缺血性卒中、蛛网膜下腔出血、轻度认知障碍、失眠障碍、癫痫以及血管性头痛的作用机制。[方法] 通过中药系统药理学数据库与分析平台(Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform，TCMSP)、Swiss Target Prediction数据库以及PubChem平台预测桂枝茯苓丸组方药物的核心活性成分及对应靶点；检索DrugBank、疾病基因网络(Disease Gene Network，DisGeNET)、基因组注释数据平台(Genome Annotation Database Platform，GeneCards)及在线人类孟德尔遗传(Online Mendelian Inheritance in Man，OMIM)数据库获取疾病相关靶点，得到药物-疾病交集靶点；采用Cytoscape 3.9.1 软件构建“ 药物-疾病-成分-靶点”网络和蛋白互作(protein-protein interaction，PPI)网络图，通过Metascape数据库对交集靶点进行核心靶点的基因本体(gene ontology，GO)功能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。利用AutoDock Vina软件对核心成分和关键靶点进行分子对接验证。[结果] 筛选去重后共获取桂枝茯苓丸核心活性成分155个，相关靶点672个，脑病靶点196个，药物-疾病交集靶点78个，其中桂枝茯苓丸“异病同治”脑病的5个核心活性成分为丹皮酚、槲皮素、芍药苷、肉桂醛、苦杏仁苷，PPI筛选得到5个关键靶点分别为白细胞介素-6(interleukin-6，IL6)、肿瘤坏死因子(tumor necrosis factor，TNF)、胰岛素(insulin，INS)、RAC-α丝氨酸/苏氨酸蛋白激酶(RAC-alpha serine/threonine-protein kinase，AKT1)、白细胞介素-1β(interleukin-1β，IL1B)，KEGG富集分析显示主要通路分别为脂质与动脉粥样硬化、流体剪切力与动脉粥样硬化、癌症中的通路、糖尿病并发症中的高级糖基化终末产物-受体(advanced glycation end products-receptor of advanced glycation end products，AGEs-RAGE)信号通路、阿尔茨海默病、神经退行性变-多发性疾病中的通路。分子对接结果显示核心活性成分和关键靶点之间结合活性较好。[结论] 本研究阐述了桂枝茯苓丸“异病同治”脑病多成分、多靶点、多通路的可能机制，为进一步了解桂枝茯苓丸的作用机制，探索新的临床应用和实验探究提供了一定的理论依据和参考。

Investigation on the Mechanism of Guizhi Fuling Pill in Treating Encephalopathy with“ Treating Different Diseases with Same Method” Based on Network Pharmacology and Molecular Docking

[Objective] To explore the mechanism of Guizhi Fuling Pill’s treating ischemic stroke(IS)， subarachnoid hemorrhage(SAH)，mild cognitive impairment(MCI)， insomnia disorder(ID)， epilepsy(EP) and vascular headaches through“ treating different diseases with the same method”， by using network pharmacology and molecular docking. [Methods] The active components and targets of Guizhi Fuling Pill were screened out and obtained from Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform(TCMSP)， Swiss Target Prediction database and PubChem platform. The targets of disease were searched from DrugBank， Disease Gene Network(DisGeNET)， Genome Annotation Database Platform(GeneCards) and Online Mendelian Inheritance in Man(OMIM). Then the common targets of drug-disease were obtained， Cytoscape 3.9.1 software was used to construct a“ drug-disease-component-target” network and protein-protein interaction(PPI) network. Gene ontology(GO) function enrichment and Kyoto Encyclopedia of Genes and Genomes(KEGG)pathway enrichment analysis of common targets were carried out by Metascape database. AutoDock Vina software was used to verify the molecular docking of core components and key targets. [Results] After screening and deleting duplicates，155 core active ingredients of Guizhi Fuling Pill，672 related targets，196 disease targets and 78 drug-disease common targets were obtained. There were 5 core active ingredients in Guizhi Fuling Pill’s“ treating different diseases with the same method” for encephalopathy， which were paeonol， quercetin，paeoniflorin， cinnamaldehyde and amygdalin. There were 5 key targets obtained by PPI screening which were interleukin-6(IL6)， tumor necrosis factor(TNF)， insulin(INS)， RAC-alpha serine/threonine-protein kinase(AKT1)， interleukin-1 beta(IL1B). KEGG pathway enrichment analysis showed that the key pathways were lipid and atherosclerosis， fluid shear stress and atherosclerosis， pathways in cancer， advanced glycation end products-receptor of advanced glycation end products(AGEs-RAGE) signaling pathway in diabetic complications， Alzheimer’s disease and pathways of neurodegeneration-multiple diseases. The molecular docking results showed that the key targets had good binding activity to the core active components. [Conclusion] The possible mechanism of multi-component， multitarget and multi-pathway of Guizhi Fuling Pill’s treating encephalopathy through“treating different diseases with the same method” was expounded， which provided a theoretical basis and reference for further understanding the mechanism of Guizhi Fuling Pill and exploring new clinical application and experimental exploration.