基于网络药理学和分子对接技术整合策略探讨芬氟拉明治疗癫痫的潜在作用机制  

Exploring the potential mechanism of fenfluramine in treating epilepsy based on network pharmacology and molecular docking

作　　者：曾娇 莫显刚 冯占辉 ZENG Jiao;MO Xiangang;FENG Zhanhui(The Affiliated Hospital of Guizhou Medical University,Guiyang(550004),Guizhou,China)

机构地区：[1]贵州医科大学附属医院神经内科,贵州贵阳550004

出　　处：《癫痫与神经电生理学杂志》2024年第4期193-198,F0002,F0003,共8页Journal of Epileptology and Electroneurophysiology

基　　金：国家自然科学基金项目(82360266);贵州省科技厅项目(黔科合基础-ZK[2023]一般395和黔科合基础-ZK[2023]一般324)。

摘　　要：目的基于网络药理学和分子对接技术探讨芬氟拉明治疗癫痫的潜在作用机制。方法从GeneCards、DisGeNET和OMIM数据库中对癫痫的相应疾病靶点进行筛查,利用drugbank、pharmmapper、swisstarget等数据库筛选芬氟拉明的药物靶点。取癫痫和芬氟拉明的交集靶点,利用STRING数据库构建蛋白相互作用网络,将其导入Cytoscape 3.9.1软件作网络拓扑分析筛选核心靶点并处理可视化。通过DAVID数据库对交集靶点进行基因本体论(GO)和京都基因与基因组百科全书(KEGG)富集分析。利用分子对接技术验证芬氟拉明与关键靶点的相互作用。结果获得139个癫痫与芬氟拉明的交集靶点基因,并根据网络拓扑分析筛选出33个核心靶点。GO分析结果显示,核心靶点主要涉及化学突触传递及信号转导等生物过程(BP);离子体膜、细胞质及质膜等细胞成分(CC);蛋白结合、神经递质受体活性等分子功能(MF)。KEGG富集分析结果显示,芬氟拉明可能通过调控多巴胺能神经突触、神经活性配体-受体相互作用及PI3K-Akt等多个信号通路治疗癫痫。分子对接结果显示,芬氟拉明与DRD2、EGFR、HSP90AA1、SLC6A4、GSK3β及GRIN2B等关键靶点稳定结合。结论本文利用网络药理学和分子对接技术分析得到芬氟拉明可能通过作用于DRD2,从而调控多巴胺能突触信号通路抑制癫痫发作,为进一步研究其治疗癫痫的具体机制提供了新的线索,亦为后续临床和实验研究提供理论基础,从而有助于开发治疗癫痫的有效新药。Objective To explore the potential mechanism of fenfluramine in treating epilepsy based on network pharmacology and molecular docking.Methods The targets of epilepsy were screened from GeneCards,DisGeNET and OMIM databases,and the targets of fenfluramine was screened from drugbank,pharmmapper and swisstarget.The targets shared by epilepsy and fenfluramine were obtained by intersecting their targets.The protein-protein interaction network was constructed by using STRING database and imported into Cytoscape 3.9.1 software,which was used to analyze hub targets and visualize the protein-protein interaction network.Biological function annotation and key target pathway analysis were performed on shared targets using DAVID database.Molecular docking was used to verify the interaction of fenfluramine with key targets.Results A total of 139 targets shared by epilepsy and fenfluramine were obtained,and 33 hub targets were identified using network topology.GO annotation showed that hub targets were involved in biological process(BP)such as chemical synaptic transmission and signal transduction,cellular component(CC)such as dendrite,cytoplasm and cell membrane,molecular function(MF)such as protein binding and neurotransmitter receptor activity.KEGG enrichment analysis showed that fenfluramine might treat epilepsy via regulating dopaminergic synaptic pathway,neuroactive ligand-receptor interaction and PI3K-Akt signaling pathway.Molecular docking results showed that fenfluramine stably bound to key targets DRD2,EGFR,HSP90AA1,SLC6A4,GSK3B and GRIN2B.Conclusion This study demonstrates that fenfluramine might act on DRD2,thus regulating dopaminergic synaptic pathway to inhibit epileptic seizures.It will provide a theoretical basis for the follow-up clinical and experimental research and contribute to the development of effectively new drugs for treating epilepsy.

关 键 词：癫痫 芬氟拉明 网络药理学 分子对接 多巴胺能突触 蛋白相互作用 

分 类 号：R742.1[医药卫生—神经病学与精神病学] R971[医药卫生—临床医学]