目的: 通过网络药理学方法探寻非甾体抗炎药(nonsteroidal anti-inflammatory drugs, NSAIDs)作为抗炎止痛药对呼吸道合胞病毒(RSV)的潜在作用机制,通过网络药理学研究筛选抗RSV的最有影响力的NSAIDs药物。方法: 将美国食品和药物管理局(FDA)批准的NSAIDs(19种活性药物和一种前药)用于本研究。通过Swiss Target Prediction和PubChem数据库收集NSAIDs的靶点,在GeneCards数据库中检索疾病RSV靶标。利用韦恩网绘制NSAIDs靶点蛋白与RSV靶点蛋白的交集,在STRING数据库对药物-疾病交集靶蛋白进行蛋白互作分析,在Cytoscape 3.9.0中对该网络进行美化。在DAVID数据库中对交集靶蛋白进行京都基因和基因组百科全书(KEGG)通路富集分析,利用微生信在线绘图工具绘制KEGG通路富集分析的气泡图,通过Cytoscape 3.9.0进行通路-靶点-成分网络分析,最后通过分子对接(AutoDock Vina)确定NSAIDs对靶蛋白的结合亲和力。结果: 共搜集到421个NSAIDs靶点,391个与RSV相关的靶点,39个重叠的靶蛋白,基因组富集分析显示了37条抗RSV的信号通路,探索出MAPK1、AKT1和MAP2K1是与B细胞受体信号通路相关性最大的靶蛋白。结论: 三种NSAIDs(舒林酸、罗非昔布、双氯芬酸)可能通过使MAPK1、AKT1和MAP2K1等相关靶蛋白失活来阻断B细胞受体信号通路,从而缓解RSV引起的支气管炎和肺炎。
Objective: To investigate the potential mechanisms of nonsteroidal anti-inflammatory drugs (NSAIDs) as anti-inflammatory analgesics against respiratory syncytial virus (RSV) through a network pharmacology approach. The most influential NSAIDs against RSV were screened through network pharmacology studies. Methods: NSAIDs (19 active drugs and one prodrug) approved by U.S. Food and Drug Administration (FDA) were used in this study. Targets for NSAIDs were collected through the Swiss Target Prediction and PubChem databases, and RSV targets were searched in the GeneCards database. The intersection of NSAIDs target proteins with RSV target proteins was mapped using Wayne's Web, protein interaction analysis of drug-disease intersection target proteins was performed in the STRING database, and the network was embellished using Cytoscape 3.9.0. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis of the intersecting target proteins was performed in the DAVID database. Bubble plotting for KEGG pathway enrichment analysis was made using the Bioinformatics drawing tool. Pathway-target-component network analysis was performed by Cytoscape 3.9.0. Finally, the binding affinity of NSAIDs to target proteins is determined by molecular docking (AutoDock Vina). Results: A total of 421 targets of NSAIDs, 391 targets associated with RSV, 39 overlapping target proteins were collected. 37 anti-RSV signaling pathways were revealed busing Genomic enrichment analysis. MAPK1, AKT1 and MAP2K1 were explored as the target proteins with the greatest relevance to the B-cell receptor signaling pathway. Conclusion: Three NSAIDs (sulforaphane, rofecoxib and diclofenac) may block the B-cell receptor signaling pathway by inactivating their related target proteins, thereby potentially alleviating RSV-induced bronchitis and pneumonia.
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