Abstract
Non-steroidal anti-inflammatory drugs (NSAIDs) showed promising clinical efficacy toward COVID-19 (Coronavirus disease 2019) patients as potent painkillers and anti-inflammatory agents. However, the prospective anti-COVID-19 mechanisms of NSAIDs are not evidently exposed. Therefore, we intended to decipher the most influential NSAIDs candidate(s) and its novel mechanism(s) against COVID-19 by network pharmacology. FDA (U.S. Food & Drug Administration) approved NSAIDs (19 active drugs and one prodrug) were used for this study. Target proteins related to selected NSAIDs and COVID-19 related target proteins were identified by the Similarity Ensemble Approach, Swiss Target Prediction, and PubChem databases, respectively. Venn diagram identified overlapping target proteins between NSAIDs and COVID-19 related target proteins. The interactive networking between NSAIDs and overlapping target proteins was analyzed by STRING. RStudio plotted the bubble chart of the KEGG (Kyoto Encyclopedia of Genes and Genomes) pathway enrichment analysis of overlapping target proteins. Finally, the binding affinity of NSAIDs against target proteins was determined through molecular docking test (MDT). Geneset enrichment analysis exhibited 26 signaling pathways against COVID-19. Inhibition of proinflammatory stimuli of tissues and/or cells by inactivating the RAS signaling pathway was identified as the key anti-COVID-19 mechanism of NSAIDs. Besides, MAPK8, MAPK10, and BAD target proteins were explored as the associated target proteins of the RAS. Among twenty NSAIDs, 6MNA, Rofecoxib, and Indomethacin revealed promising binding affinity with the highest docking score against three identified target proteins, respectively. Overall, our proposed three NSAIDs (6MNA, Rofecoxib, and Indomethacin) might block the RAS by inactivating its associated target proteins, thus may alleviate excessive inflammation induced by SARS-CoV-2.
Highlights
Non-steroidal anti-inflammatory drugs (NSAIDs) showed promising clinical efficacy toward COVID19 (Coronavirus disease 2019) patients as potent painkillers and anti-inflammatory agents
Among the selected NSAIDs, nineteen NSAIDs were found as an active drug, and one "nabumetone" was a prodrug, and its metabolite form is 6-methoxy-2-naphthylacetic acid (6MNA)
This study suggests that 6MNA, Rofecoxib, and Indomethacin are the most potent NSAIDs against COVID-19
Summary
Non-steroidal anti-inflammatory drugs (NSAIDs) showed promising clinical efficacy toward COVID19 (Coronavirus disease 2019) patients as potent painkillers and anti-inflammatory agents. FOXO FOrkhead boX protein O GnRH Gonadotropin-Releasing Hormone HIV Human Immunodeficiency Virus IFN-γ Interferon gamma IL-4 Interleukin 4 IL-10 Interleukin 10 IL-17 Interleukin 17 KEGG Kyoto Encyclopedia of Genes and Genomes MAPK Mitogen-Activated Protein Kinase MAPK8 Mitogen-Activated Protein Kinase 8 MAPK10 Mitogen-Activated Protein Kinase 10 MDT Molecular Docking Test NF-κB Nuclear Factor Kappa-light-chain-enhancer of activated B cells NLR Nod-Like Receptor NLRs Nod-Like Receptors NSAIDs Non-Steroidal Anti-Inflammatory Drugs PPAR Peroxisome Proliferator-Activated Receptors PPARα Peroxisome Proliferator-Activated Receptor-alpha PPARγ Peroxisome Proliferator-Activated Receptor-gamma PPARβ/δ Peroxisome Proliferator-Activated Receptor-beta/delta PAMPs Pathogen-Associated Molecular Patterns PPI Protein–protein interaction RA Rheumatoid Arthritis RAS Renin Angiotensin System RLR RIG-I-Like Receptor RLRs RIG-I-Like Receptors SARS-CoV-2 Severe Acute Respiratory Syndrome CoronaVirus 2 SEA Similarity Ensemble Approach STN Signaling pathway-Target protein-NSAID STP Swiss Target Prediction TLR Toll-like receptor TLRs Toll-like receptors TNF Tumor Necrosis Factor TNF-α Tumor Necrosis Factor-Alpha TPSA Topological Polar Surface Area VEGF Vascular Endothelial Growth Factor VEGFA Vascular Endothelial Growth Factor A WHO World Health Organization WNT Wingless/Integrated. WHO announced that no evidence of unwanted side effects was reported, the risk of death with NSAIDs’ administration in COVID-19 patients[9]
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