基于网络药理学和分子对接技术研究丹参治疗非酒精性脂肪性肝炎的作用机制

A study on the mechanism of treating nonalcoholic steatohepatitis with Danshen based on network pharmacology and molecular docking technology

目的:非酒精性脂肪性肝炎的发展不仅是一个重要的病理阶段,而且也是治疗的关键时期,其发展可能会发生可逆的变化,但也可以演变为纤维化、肝硬化或原发性肝癌。网络药理学是对“药物-成分-靶点-疾病”进行直接的数据分析,表明一味药可以通过多途径协同作用于人体的药效机制。而分子对接技术被广泛认为是药物设计有力的工具,它能够从分子水平预测药物与疾病的结合构象。通过对网络药理学、分子对接的研究,探讨丹参在非酒精性脂肪性肝炎的作用机制。方法:借助中药系统药理学数据库与分析平台(TCMSP)、Gene Cards、DisGeNET、TTD、DrugBank和OMIM等数据库,确定丹参主要活性成分及治疗非酒精性脂肪性肝炎的作用靶点。研究使用Cytoscape3.7.2软件系统,构建成分-靶点网络图,并使用Venny 2.1.0在线工具取其交集靶点,再使用STRING系统进行蛋白质-蛋白质相互作用网络分析,并使用Metascape平台进行基因本体论(GO)和京都基因与基因组百科全书(KEGG)富集分析,最终用AutoDock Tools进行分子对接,运用PyMOL软件对结果进行可视化分析。结果:得到丹参干预非酒精性脂肪性肝炎的活性成分共计62个,α-香树精、丹参酮ⅡA、木犀草素、鼠尾草酚酮等成分较为关键;与非酒精性脂肪性肝炎有关的靶点86个,其中最为重要的是为前列腺素氧化环化酶2(Prostaglandin-Endoperoxide Synthase 2,PTGS2)、核受体辅激活蛋白1(Nuclear Receptor Coactivator 1,NCOA1)、β2肾上腺素受体(Adrenoceptor Beta 2,ADRB2)等;GO显示出细胞对脂质的反应、氧气水平降低的反应等;KEGG主要与缺氧诱导因子-1(Hypoxia Inducible Factor-1,HIF-1)、松弛素、过氧化物酶体增殖物激活受体(Peroxisome Proliferator Activated Receptor,PPAR)、腺苷酸活化蛋白激酶(AMP-activated Protein Kinase,AMPK)、Wnt、核因子-κB(Nuclear Factor-κB,NF-κB)等信号途径相关;分子对接也证实了两者间有较好的结合力。结论:丹参可通过多分子、多途径发挥改善非酒精性脂肪性肝炎的作用,包括癌症途径、脂质和动脉粥样硬化、内分泌抵抗、胰岛素抵抗、脂肪细胞中脂解的调节等机制。

Objective:The development of nonalcoholic steatohepatitis(NASH)is not only an important pathological stage,but also a critical period of treatment,the development of which can undergo reversible changes,but can also evolve into fibrosis,cirrhosis or primary liver cancer.Network pharmacology is a direct data analysis of drug-component-target-disease,showing that the pharmacodynamic mechanism of a drug can synergistically act on the human body through multiple pathways.Molecular dockingO technology is widely regarded as a powerful tool for drug design,which can predict the binding conformation of drugs and diseases at the molecular level.Through the study of network pharmacology and molecular docking,the mechanism of action of Danshen(Radix et Rhizoma Salviae Miltiorrhizae)in NASH was explored.The mechanism of action of Danshen in NASH was explored by network pharmacology and molecular docking.Methods:With the help of databases such as TCMSP,GeneCards,DisGeNET,TTD,DrugBank and OMIM,the main active components of Danshen and the therapeutic targets for NASH were determined.Using the Cytascape 3.7.2 software system,a component target network diagram was created,the Venny 2.1.0 online tool was used to obtain its intersection targets,then the STRING system was used for PPI network analysis,and the Metascape platform was used for GO and KEGG enrichment analysis.Finally,AutoDock Tools was used for molecular docking,and PyMOL software was used to visualize the results.Results:A total of 62 active ingredients were obtained from Danshen for intervention in NASH,the components such asα-amyrin,tanshinone iia,luteolin,salviolone are more critical.There are 86 targets related to NASH,among which the most important are PTGS2,NCOA1,ADRB2,etc..GO showed cellular responses to lipids,decreased oxygen levels,and so on.KEGG is mainly related to signal pathways such as HIF-1,Relaxin,PPAR,AMPK,Wnt and NF-κB.Molecular docking also confirmed a good binding force between the two.Conclusion:Danshen can improve NASH through multiple molecules and pathways,including cancer pathway,lipid and atherosclerosis,endocrine resistance,insulin resistance,regulation of lipolysis in adipocytes and other mechanisms.