基于网络药理学探讨瓜拉纳治疗阿尔兹海默症的潜在作用机制

Potential targets and mechanisms of Guarana in the treatment of Alzheimer’s disease based on network pharmacology

目的通过网络药理学方法及分子对接研究瓜拉纳治疗阿尔茨海默症(AD)的主要活性成分及其潜在作用机制。方法基于文献挖掘获取瓜拉纳的化学成分并进行化学成分的类药性分析,运用本草组鉴(HERB)、中药系统药理学数据库与分析平台(TCMSP)等数据库获取瓜拉纳活性成分的潜在作用靶点并关联靶点相关疾病。利用GeneCards人类基因数据库、DisGeNET数据库收集阿尔兹海默症的疾病相关基因,利用韦恩图构建瓜拉纳治疗阿尔兹海默症的潜在靶点,运用CytoScape软件构建相应的网络互作图。找出运用STRING在线数据库建立关键靶点之间的蛋白质-蛋白质相互作用(PPI)网络图,并对关键靶点蛋白进行基因本体(GO)及京都基因与基因组百科全书(KEGG)通路富集分析。使用AutoDock软件对重要活性化合物与关键靶点进行分子对接验证。结果瓜拉纳治疗阿尔兹海默症潜在靶点共140个。PPI蛋白互作网络分析发现白细胞介素6(IL-6)、肿瘤坏死因子(TNF)、胰岛素(INS)、丝裂原活化蛋白激酶3(MAPK3)、转录因子(JUN)、肿瘤蛋白p53(TP53)、胱天蛋白酶3(CASP3)、c-Fos蛋白质(FOS)、抗氧化酶(CAT)、连环蛋白β-1(CTNNB1)等可能是瓜拉纳治疗阿尔兹海默症的关键靶点。GO富集分析和KEGG通路分析发现瓜拉纳治疗阿尔兹海默症的潜在作用是于细胞膜外以化合物与蛋白酶结合的形式发生的。分子对接结果显示瓜拉纳中多种化合物小分子与TNF、IL-6、MAPK3、FOS等靶蛋白均具有较低的结合能。结论瓜拉纳对治疗阿尔兹海默症具有多靶点协同作用的特点,其治疗AD的关键作用靶点可能是IL-6、TNF和MAPK3,它们可能通过与β-淀粉样蛋白结合的生物学过程和癌症相关信号通路发挥治疗作用,本研究为瓜拉纳治疗阿尔兹海默症进一步的研究提供了科学依据和参考。

Objective To dig the main active components and predict potential mechanisms of Guarana in the treatment of Alzheimer’s disease(AD)by network pharmacology method and molecular docking.Methods By digging into papers relating to this topic,chemical components in Guarana were obtained and used for drug-likeness analysis.Databases including HERB and Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform(TCMSP)were used to obtain potential targets that the active components in Guarana might have effects on,and to find out diseases in association with the potential targets.Other databases such as GeneCards,a human gene database,and DisGeNET were used to identify the genes relating to AD,and a Wayne diagram was drawn to get the intersected targets in Guarana and AD.Subsequently,CytoScape software was adopted for the construction of a Guarana-intersected targets-AD map.After that,the intersected targets were uploaded to the Search Tool for the Retrieval of Interaction Gene/Proteins(STRING)database to acquire a protein-protein interaction(PPI)network diagram.Then,the key target proteins were analyzed by Gene Ontology(GO)and Kyoto Encyclopedia of Genes and Genomes(KEGG).In terms of molecular docking verification,AutoDock software was used to verify whether the crucial active compounds of Guarana’s components could bind to the key targets.Results A total of 140 potential targets for Guarana to treat AD were obtained.The results of PPI network analysis showed that interleukin 6(IL-6),tumor necrosis factor(TNF),insulin(INS),mitogen-activated protein kinase 3(MAPK3),transcription factor(JUN),cell tumor antigen p53(TP53),caspase3(CASP3),protein c-Fos(FOS),catalase(CAT),and Catenin beta-1(CTNNB1)might be the key targets of Guarana in the treatment of AD.It was found by GO and KEGG analyses that the mechanism of Guarana in the treatment of AD might be the bindings between Guarana compounds and protease outside the cell membranes.The molecular docking results showed that the small molecules of various components in Guarana binding to target proteins such as TNF,IL-6,MAPK3,and FOS needed relatively less energy.Conclusion The treatment of AD with Guarana involves the participation of multiple targets,among which IL-6,TNF,and MAPK3 might be the key ones.These key targets might take effects through the biological process in their bindings toβ-amyloid and involving signaling pathways in cancer.Hopefully,our research could offer some scientific foundations as well as references for in-depth studies on the treatment of AD with Guarana.