基于网络药理学与分子对接技术探讨氟西汀抗抑郁的新作用机制

New Mechanism of Antidepressant Effect Exploration of Fluoxetine Based on Network Pharmacology and Molecular Docking Technology

目的通过网络药理学和分子对接技术探究氟西汀治疗抑郁症的关键靶标及新的作用机制。方法检索Swiss Target Prediction数据库,获得氟西汀作用靶点;检索HOME-NCBI-GENE和Gene Cards数据库,获取抑郁症治疗靶点;利用Cytoscape Version3.7.2软件和String数据库绘制蛋白质相互作用网络图(PPI),采用DAVID数据库对氟西汀抗抑郁的潜在靶点进行GO功能富集分析和KEGG通路分析;应用Auto Dock 4.2软件对核心靶点进行分子对接验证。结果通过筛选得到AKT1、EGFR、EGF、MTOR、PIK3CA、CASR、DRD2、HTR1A等8个关键靶点;GO功能富集分析(P<0.05)得到生物过程条目485个,细胞组成条目46个,分子功能条目64个;KEGG通路富集分析筛选得到41条(P<0.05)信号通路,主要涉及的通路有神经活性配体受体相互作用、mTOR信号通路、神经营养素信号通路、VEGF信号通路等;分子对接结果显示氟西汀与靶蛋白AKT1、CASR具有较好的亲和力。结论氟西汀治疗抑郁症具有“多靶标-多途径”的调节特点。

Objective To explore key targets and new action mechanisms of fluoxetine in treatment of depression based on network pharmacology and molecular docking technology.Methods The paper retrieved Swiss Target Prediction database to obtain fluoxetine action targets;retrieved HOME-NCBI-GENE and Gene Cards databases to obtain treatment targets of depression;drew protein interaction network diagrams(PPI)through Cytoscape Version 3.7.2 software and String database,and conducted GO functional enrichment analysis and KEGG pathway analysis on potential antidepressant targets of fluoxetine through DAVID database,molecular docking verification of core targets through Auto Dock 4.2 software.Results The study identified 8 key targets through screening,including AKT1,EGFR,EGF,MTOR,PIK3CA,CASR,DRD2 and HTR1A,485 biological process entries,46 cell composition entries and 64 molecular functional entries based on GO functional enrichment analysis(P<0.05),screened 41 signaling pathways based on KEGG pathway enrichment analysis(P<0.05),mainly involving neural active ligand receptor interactions,mTOR signaling pathway,neurotrophin signaling pathway,VEGF signaling pathway and etc.Molecular docking results showed fluoxetine had good affinity with target proteins AKT1 and CASR.Conclusion Fluoxetine can have regulatory characteristics of"multi target multi pathway"in treatment of depression.