基于网络药理学和分子对接探讨熟地黄—黄精治疗阿尔茨海默病的作用机制

Exploring the mechanism of Rehmannia Radix Praeparata-Rhizoma polygonati in the treatment of Alzheimer’s disease based on network pharmacology and molecular docking

目的 整合网络药理学、分子对接技术探究熟地黄—黄精治疗阿尔茨海默病(Alzheimer’s disease, AD)的作用机制。方法 在中药系统药理数据库(Traditional Chinese Medicine System Pharmacology, TCMSP)数据库中收集熟地黄、黄精化学成分和潜在作用靶点,在在线人类孟德尔遗传(online mendelian inheritance in man, OMIM)、治疗靶点(therapeutic target database, TTD)、GeneCards、Drug Bank数据库收集AD疾病靶点基因,运用Cytoscape3.9.1构建“中药—成分—靶点”网络;将熟地黄、黄精与AD的交集靶点基因上传至STRING数据库中分析核心靶点基因;将交集靶点上传至DAVID数据库中进行GO和KEGG富集分析,并通过分子对接检测核心化学成分和核心靶点基因的结合能力。结果 在熟地黄、黄精中共筛选出13个化学成分,其中薯蓣皂苷、3′-甲氧基黄豆苷、豆甾醇、黄芩苷、β-谷甾醇为核心化学成分;AD相关靶点共筛选出2471个,熟地黄、黄精与AD的交集靶点共有68个;PPI分析显示,蛋白激酶B(protein kinase B,Akt1)、前列腺素G/H合成酶2(prostaglandin G/H synthase 2,PTGS2)、凋亡相关蛋白Caspase-3等为核心交集靶点基因;GO分析显示,生物过程主要涉及对含氧化合物、对化学物质的反应等,细胞组成主要涉及神经元投射、神经元部分、躯体树突间室等,分子功能主要涉及酶结合、G蛋白偶联胺受体活性、相同蛋白质结合等;KEGG分析结果显示,核心靶点基因涉及的通路主要为内分泌抵抗、麻疹、雌激素信号通路、凋亡、流体剪切应力与动脉粥样硬化等;分子对接结果显示,核心化学成分黄芩苷、β-谷甾醇、3′-甲氧基黄豆苷与核心靶点结合效能高。结论 熟地黄、黄精防治AD的成分主要为黄芩苷、β-谷甾醇、3′-甲氧基黄豆苷等,这些成分可通过调节10个核心靶点基因发挥防治AD的作用,其机制可能与凋亡、雌激素通路等5个途径有关。

Objective Study on the mechanism of action of Rehmannia Radix Praeparata-rhizoma polygonati in the treatment of Alzheimer’s disease(AD)by integrating network pharmacology and molecular docking technology.Methods The chemical constituents and potential targets of Rehmannia Radix Praeparata and rhizoma polygonati were collected from traditional Chinese medicine system pharmacology(TCMSP)database,and the AD disease target genes were collected from online mendelian inheritance in man(OMIM),therapeutic target database(TTD),GeneCards and Drug Bank databases.Cytoscape3.9.1 was used to construct the network of“traditional Chinese medicine-constituent-target”.The intersection target genes of Rehmannia Radix Praeparata,rhizoma polygonati and AD were uploaded to the STRING database to analyze the core target genes.The intersection targets were uploaded to the DAVID database for GO and KEGG enrichment analysis,and the binding ability of core chemical components and core target genes were detected by molecular docking.Results A total of 13 chemical components were screened out from cooked Rehmannia Radix Praeparata and rhizoma polygonati,among which diosgenin,3′-methoxy daidzein,stigmasterol,baicalin andβ-sitosterol were the core chemical components.A total of 2471 AD related targets were selected,and 68 intersection targets of Rehmannia Radix Praeparata,rhizoma polygonati and AD were identified.The result of PPI analysis showed that protein kinase B(AKT1),prostaglandin G/H synthase 2(PTGS2),Caspase-3(CASP3),etc.were the core intersection target genes.The result of GO analysis showed that biological processes mainly involved reactions to oxygen-containing compounds and chemical substances,cell composition mainly involved neuronal projection,neuron parts,and somatic dendrite compartments,molecular functions mainly involved enzyme binding,G protein-coupled amine receptor activity,and same protein binding,etc.The result of KEGG analysis showed that the pathways involved in the core target genes were mainly endocrine resistance,measles,estrogen signaling pathway,apoptosis,fluid shear stress and atherosclerosis,etc.The result of Molecular docking showed that baicalin,β-sitosterol and 3′-methoxydaidzein had high binding efficiency to the core target.Conclusion The main components of Rehmannia Radix Praeparata and rhizoma polygonati in the treatment of AD are baicalin,β-sitosterol,3′-methoxysalicylic acid,etc.These components can play a significant role in the prevention and treatment of AD by regulating 10 core target genes,and its mechanism may be related to 5 pathways such as apoptosis and estrogen pathway.