艾拉莫德治疗痛风的网络药理学机制研究

The network pharmacological mechanism of iguratimod in the treatment of gout

目的:通过网络药理学及分子对接方法探讨艾拉莫德(iguratimod,IGU)治疗痛风性关节炎(gout,以下简称痛风)的作用机制。方法:从Genecards,DisGeNET等数据库中获取痛风的疾病靶点;IGU的潜在作用靶点通过PharmMapper进行预测;利用信息进行药物-成分-靶点网络图的绘制;通过David在线平台进行基因本体(gene ontology,GO)分析及京都基因与基因组百科全书(Kyoto encyclopedia of genes and genomes,KEGG)通路预测IGU治疗痛风可能的信号通路;String在线网站和Cytoscape软件网络应用分析构建蛋白质相互作用网络(PPI)并筛选出核心基因(hub gene)。最后通过Autodock Tool软件和PyMOL软件完成痛风核心靶标与IGU相应化合物的分子对接验证。结果:从上述数据库中共筛选出292种IGU化合物的潜在活性成分、1741种痛风潜在疾病靶标和70种交叉靶标。网络拓扑分析确定了10个中枢目标,如SRC,AKT1,MAPK14,PPARG和IGF1等。Go富集分析主要集中在凋亡负调控、血管内皮生长因子受体信号通路等。KEGG富集分析表明:PI3K-Akt信号通路、丝裂原活化蛋白激酶(MAPK)信号通路、NOD样受体信号通路、肿瘤坏死因子(TNF)信号通路和Th17细胞分化可能在IGU治疗痛风药理机制中发挥重要作用。分子对接验证提示核心基因AKT1,MAPK14与IGU具有较好结合能。结论:本研究初步揭示了IGU作用于痛风的蛋白质靶点,探讨了其可能通过多途径在痛风治疗中发挥调节免疫、控制炎症的治疗作用。

Objective:To explore the mechanism of action of Iguratimod(IGU)in the treatment of Gout by network pharmacology and molecular docking.Methods:Disease targets for Gout were retrieved from databases such as Genecards,DisGeNET;The potential acting targets of IGU were predicted by pharmmapper;We also mapped drug-ingredient-target to conduct network diagram.Gene ontology(GO)and Kyoto Encyclopedia of Genes and Genomes(KEGG)enrichment analyses were carried out by David online platform.Hub target genes among the intersections of the potential targets(IGU)and related genes(Gout)were constructed and screened out using protein-protein interactions(PPI)network through String database and Cytoscape databases.The molecular docking validation of Gout targets with the active compounds of IGU was finally accomplished by AutodockTool and PyMOL softwares.Results:A total of 292 potential active components of IGU compounds,1741 potential disease targets of Gout and 70 cross targets were screened from the above database.Network topology analysis identified 10 hub gene targets,such as SRC,AKT1,MAPK14,PPARG,and IGF1.GO enrichment analysis mainly focused on the negative regulation of apoptotic process and vascular endothelial growth factor receptor signaling pathway.KEGG enrichment analysis illustrated that the PI3 K-Akt signaling pathway,mitogen-activated protein kinases(MAPK)signaling pathway,NOD-like receptor signaling pathway,tumor necrosis factor(TNF)signaling pathway,and Th17 cell differentiation might play an important role in the pharmacological mechanism of IGU in the treatment of Gout.Molecular docking suggested that the hub genes AKT1 and MAPK14 had better binding energies with IGU.Conclusion:This study preliminarily revealed the protein targets affected by IGU when acting on Gout,and found that it may play a potential therapeutic role by multi-pathway in the treatment of Gout.