基于网络药理学及计算机辅助药物设计研究护肝宁片治疗非酒精性脂肪性肝病的作用机制  被引量:3

Research of the mechanism of Huganning tablet in the treatment of nonalcoholic fatty liver disease based on network pharmacology and computer-aided drug design

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作  者:陈聪 周香辉 张兵 彭彦芬 杨新平[1] 余启明 谭相端[1] CHEN Cong;ZHOU Xiang-hui;ZHANG Bing;PENG Yan-fen;YANG Xin-ping;YU Qi-ming;TAN Xiang-duan(College of Pharmacy,Guilin Medical University,Guilin 541199,China)

机构地区:[1]桂林医学院药学院,广西桂林541199

出  处:《药学学报》2023年第3期695-710,共16页Acta Pharmaceutica Sinica

基  金:国家自然科学基金资助项目(82060627);广西自然科学基金项目(2020GXNSFAA159149);广西研究生教育创新计划项目(YCSW2022367)。

摘  要:基于网络药理学与计算机辅助药物设计探讨护肝宁片(Huganning tablet,HGNP)治疗非酒精性脂肪性肝病(nonalcoholic fatty liver disease,NAFLD)的作用机制。通过TCMSP数据库、Swiss Target Prediction数据库、中国药典(2015版)及文献检索确定HGNP的潜在活性成分及作用靶点,并借助GeneCards数据库检索到的NAFLD疾病相关靶点进行交集整合,获取HGNP治疗NAFLD的潜在作用靶点。运用R软件中bioconductor生物信息软件包对潜在作用靶点进行GO(geneontology)和KEGG(Kyoto encyclopedia of genes and genomes)富集分析,利用Cytoscape软件构建出“潜在活性成分-关键靶点-通路”网络,整体探究潜在活性成分与关键靶点、通路、疾病间的关联。基于上述分析结果,采用Discovery Studio 2020软件将HGNP中的潜在活性成分与网络图中度值排名靠前的关键靶点进行分子对接分析,并进行分子动力学模拟、结合自由能计算、类药性分析和ADMET性质预测。体外实验使用HepG2细胞构建脂肪变性模型,根据细胞油红O染色与甘油三酯(triglyceride,TG)含量检测实验,验证5个关键化合物对肝细胞脂肪变性的改善作用。筛选获得141个潜在活性成分和151个潜在作用靶点,通过GO和KEGG富集分析,分别得到2526个条目和151条通路。分子对接结果显示,异鼠李素(isorhamnetin)、丹酚酸B(salvianolic acid B)、大黄素(emodin)、白藜芦醇(resveratrol)、大黄酸(rhein)5个成分与关键靶点[维甲酸受体RXR-α(retinoic acid receptor RXR-alpha,RXRA)、肿瘤坏死因子(tumor necrosis factor,TNF)、糖原合酶激酶(glycogen synthase kinase-3 beta,GSK3B)、丝氨酸/苏氨酸蛋白激酶1(serine/threonine-protein kinase 1,AKT1)]显示出较强的结合能力,推测为HGNP治疗NAFLD的关键化合物。根据分子动力学模拟学模拟和结合自由能计算结果,进一步验证了异鼠李素、丹酚酸B与关键靶点的结合具有较好的结构稳定性及结合亲和力。通过类药性In this study,we explored the mechanism of Huganning tablet(HGNP)in the treatment of nonalcoholic fatty liver disease(NAFLD)based on network pharmacology and computer-aided drug design.Firstly,the potential ingredients and targets of HGNP were identified from TCMSP database,Swiss Target Prediction database,Chinese pharmacopoeia(2015)and literatures,and then the targets of HGNP intersected with NAFLD disease targets that obtained in GeneCards database to acquired potential targets.The bioconductor bioinformatics package of R software was used for gene ontology(GO)enrichment and Kyoto encyclopedia of genes and genomes(KEGG)enrichment analysis.The network of“potential ingredient-key target-pathway”was formed in Cytoscape software to study the interactions between potential ingredients of HGNP,key targets,pathways and NAFLD.Based on the results of network pharmacology,the molecular docking analysis of the key targets and potential active ingredients in HGNP tablets with top degree in the network was conducted using Discovery Studio 2020 software,followed by molecular dynamics simulations,binding free energy calculation,drug-likeness properties analysis and ADMET(absorption,distribution,metabolism,excretion and toxicity)properties prediction.In vitro,HepG2 cells were used to establish steatosis model,and the effects of five key compounds on hepatocyte steatosis were analyzed by oil red O staining and triglyceride(TG)content determination.The results showed that 141 ingredients and 151 potential targets were obtained.A total of 2526items and 151 pathways were identified by GO and KEGG enrichment analysis.The molecular docking suggested that five components,isorhamnetin,salvianolic acid B,emodin,resveratrol and rhein,exhibited strong binding ability with key targets[retinoic acid receptor RXR-alpha(RXRA),tumor necrosis factor(TNF),glycogen synthase kinase-3 beta(GSK3B),serine/threonine-protein kinase 1(AKT1)].It was further verified that isorhamnetin and salvianolic acid B bind to key targets with good structural st

关 键 词:护肝宁片 非酒精性脂肪性肝病 网络药理学 计算机辅助药物设计 作用机制 

分 类 号:R966[医药卫生—药理学]

 

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