基于网络药理学、分子对接和孟德尔随机化探讨拉莫三嗪抗重度抑郁症的作用机制

Exploring the mechanism of lamotrigine in treatment of major depressive disorder based on network pharmacology,molecular docking,and Mendelian randomization

目的探索拉莫三嗪抗重度抑郁症(MDD)的作用机制。方法收集拉莫三嗪的药物靶点与MDD的治疗靶点信息进行交集靶点基因分析和蛋白质-蛋白质相互作用筛选,通过基因本体论和京都基因与基因组百科全书富集分析确定与拉莫三嗪抗MDD相关的各种生物途径,用分子对接技术对筛选的核心靶点进行初步验证,使用OpenGWAS数据库中的γ-氨基丁酸受体相关蛋白样1(GABARAPL1)和MDD的全基因组关联分析数据进行孟德尔随机化进一步验证。结果确定了与拉莫三嗪抗MDD相关的生物途径,包括γ-氨基丁酸(GABA)能突触、尼古丁成瘾、谷氨酸能突触、逆行内源性大麻素信号传导等生物途径。分子对接显示:拉莫三嗪与GABRA1、GABRB2、GABRA6、GABRD、GABRG2、GABRG1、GABRA5、GABRA4、GABRB3和GABRA2受体的结合能均≤-5.8kCal·mol^(-1),其中GABRB3受体与拉莫三嗪的结合能最强,为-9.5kCal·mol^(-1)。GABARAPL1全基因组关联分析数据中,303个单核苷酸多态性与GABARAPL1相关(P<5×10^(-6)),经筛选保留了15个单核苷酸多态性用于孟德尔随机化分析,分析结果表明,GABA受体可能是MDD的重要治疗靶点。结论拉莫三嗪可能通过作用于GABA受体产生抗MDD的作用,为进一步的拉莫三嗪抗MDD临床应用提供了研究基础。

Objective To explore the mechanism of action of lamotrigine in the treatment of major depressive disorder(MDD).Methods Information on the drug targets of lamotrigine and the therapeutic targets of MDD were collected for intersection target gene analysis and protein-protein interaction screening.Various biological pathways related to lamotrigine in treatment of MDD were determined through gene ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analysis.The screened core targets were preliminarily validated using molecular docking technology.Further validation of Mendelian randomization was conducted using genome-wide association analysis data from gamma-aminobutyric acid recep tor-associated protein-like 1(GABARAPL1)and MDD in the OpenGWAS database.Results The biological pathways related to lamotrigine in treatment of MDD werei identified,which included gamma-aminobutyric acid(GABA)ergic synapses,nicotine addiction,glutamatergic synapses,endogenous cannabinoid signaling.Molecular docking showed that the docking energy of lamotrigine with GABRA1,GABRB2,GABRA6,GABRD,GABRG2,GABRG1,GABRA5,GABRA4,GABRB3,and GABRA2 receptors was≤-5.8 kCal·mol^(-1).Among them,the GABRB3 receptor showed the strongest docking energy with lamotrigine,which was-9.5 kCal·mol^(-1).In the genome-wide association analysis data of GABARAPL1,303 single nucleotide polymorphisms were associated with GABARAPLI(P<5×10^(-6)).15 single nucleotide polymorphisms were screened and retained for Mendelian randomization analysis,and the results showed that GABA receptors may be an important therapeutic target for MDD.Conclusion The treatment of MDD with lamotrigine may be achieved by acting on GABA receptors,which provided a research basis for the clinical application of lamotrigine in treating MDD.