Background: Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) showed promising clinical efficacy toward COVID-19 patients as painkillers and anti-inflammatory agents; however, the anti-COVID-19 mechanisms of NSAIDs are not exposed. Therefore, we evaluated the most potent NSAIDs candidates and their novel mechanism(s) against COVID-19 by network pharmacology.

Method: Genes related to selected NSAIDs and COVID-19 related genes were identified by Similarity Ensemble Approach, Swiss Target Prediction, and PubChem databases. Venn diagram identified overlapping genes between NSAIDs and COVID-19 related genes. The interactive networking between NSAIDs and overlapping genes was analyzed by STRING. RStudio plotted the bubble chart of KEGG pathway enrichment analysis of overlapping genes. Finally, binding affinity of NSAIDs against target genes was determined through molecular docking analysis.

Results: Geneset enrichment analysis exhibited 26 signaling pathways against COVID-19, and inhibition of proinflammatory stimuli of tissues and/or cells by inactivating RAS signaling pathway was identified as the key anti-COVID-19 mechanism of NSAIDs. MAPK8, MAPK10, and BAD genes were explored as the associated genes of RAS. 6MNA, refecoxib, and indomethacin revealed promising binding affinity with highest docking score against three genes, respectively.

Conclusions: Overall, our proposed three NSAIDs may possibly block RAS by inactivating its associated genes, thus may alleviate excessive inflammation induced by SARS-CoV-2. Recently, clinicians recommended indomethacin as a drug of interest against COVID-19. Our study presents that indomethacin is a potent therapeutic candidate among all other NSAIDs to treat COVID-19 symptoms. However, these results provide scientific evidence, plausible mechanism, target genes, and potential NSAIDs candidates against COVID-19.