基于网络药理学和分子对接探讨千层纸素A治疗椎间盘退变的分子机制

Network Pharmacology Prediction and Molecular Docking-Based Strategy to Discover the Potential Pharmacological Mechanism of Oroxylin A Against Intervetebral Disc Degeneration

目的运用网络药理学及分子对接技术探讨千层纸素A治疗椎间盘退变的作用机制。方法通过PharmMapper、SwissTarget Prediction和Similarity ensemble approach数据库获取千层纸素A的药物作用靶点。在GeneCards和在线人类孟德尔遗传数据库搜索椎间盘退变疾病相关靶点。在此基础上,将千层纸素A的作用靶点与椎间盘退变疾病靶点取交集得到千层纸素A对椎间盘退变的潜在治疗靶点。运用在线String数据库和Cytoscape 3.8.0软件构建蛋白相互作用网络,运用R语言对共同靶点进行基因本体(GO)和京都基因与基因组百科全书(KEGG)富集分析,使用AutoDock vina软件对千层纸素A与关键靶点进行虚拟对接。结果通过筛选共得到35个千层纸素A对椎间盘退变的潜在治疗靶点。靶点涉及的通路主要包括PI3K/AKT信号通路、IL-17信号通路、TNF信号通路以及糖尿病并发症中的AGE-RAGE信号通路。结合蛋白相互作用网络和KEGG富集分析共得到白细胞介素-6(IL-6)、血管内皮生长因子A(VEGFA)、表皮生长因子受体(EGFR)和基质金属蛋白酶9(MMP9)4个核心靶点,与千层纸素A进行分子对接,结果显示亲和力均小于-5 kcal·mol-1,分子对接结果良好。结论本研究采用网络药理学和分子对接的方法,揭示出千层纸素A可能通过抑制髓核细胞凋亡、抑制细胞外基质降解、抗炎和抗血管生成发挥多靶点和多通路的抗椎间盘退变作用,为后续研究其分子机制奠定了基础。

Objective To explore the mechanism of oroxylin A in the treatment of intervertebral disc degeneration by network pharmacology and molecular docking technology.Methods PharmMapper database,SwissTarget Prediction database and Similarity ensemble approach database were used to obtain the target genes of oroxylin A.Related genes of intervertebral disc degeneration were searched in GeneCards and Online Mendelian Inheritance in Man databases.Based on this,the target genes of oroxylin A and the target genes of intervertebral disc degeneration were intersected to obtain the potential target genes of oroxylin A in the treatment of intervertebral disc degeneration.The String database and Cytoscape 3.8.0 software were used to construct the protein-protein interaction network,and the R language was used to conduct Gene Ontology(GO)and Kyoto Encyclopedia of Genes and Genomes(KEGG)enrichment analysis.The AutoDock vina software was used to conduct molecular docking between oroxylin A and hub genes.Results A total of 35 potential target genes of oroxylin A for the treatment of intervertebral disc degeneration were obtained through screening.The related signaling pathways mainly involved PI3K/AKT signaling pathway,IL-17 signaling pathway,TNF signaling pathway and AGE-RAGE signaling pathway in diabetic complications.Combined with protein-protein interaction network and KEGG analysis,four hub genes including interleukin 6(IL-6),vascular endothelial growth factor A(VEGFA),epidermal growth factor receptor(EGFR)and matrix metallopeptidase 9(MMP9)were obtained,and molecular docking was performed between oroxylin A and hub geens.The results showed that the binding affinities were all less than-5 kcal·mol-1.Conclusion This study predicted the mechanism of oroxylin A in the treatment of intervertebral disc degeneration using network pharmacology and molecular docking methods,suggesting that oroxylin A has the characteristics of multi-target and multi-pathway in the treatment of intervertebral disc degeneration via inhibiting apoptosis of nucleus pulposus cells,inhibiting degradation of extracellular matrix,anti-inflammation and anti-angiogenesis,which lays a foundation for the follow-up study of its molecular mechanism.