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Potential inhibitors of the main protease of SARS-CoV-2 and modulators of arachidonic acid pathway: Non-steroidal anti-inflammatory drugs against COVID-19

  • Sisakht, Mohsen1
  • Solhjoo, Aida2
  • Mahmoodzadeh, Amir3
  • Fathalipour, Mohammad4
  • Kabiri, Maryam2
  • Sakhteman, Amirhossein2, 5
  • 1 Department of Biochemistry, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
  • 2 Department of Medicinal Chemistry, School of Pharmacy, Shiraz University of Medical Sciences, Shiraz, Iran
  • 3 Feinberg Cardiovascular Research Institute, Feinberg School of Medicine, Northwestern University, Chicago, USA
  • 4 Department of Pharmacology and Toxicology, Faculty of Pharmacy, Hormozgan University of Medical Sciences, Endocrinology and Metabolic Research Center, Hormozgan University of Medical Sciences, Bandar Abbas, Iran
  • 5 Institute of Biomedicine, University of Eastern Finland, Kuopio, Finland
Published Article
Computers in Biology and Medicine
Elsevier Ltd.
Publication Date
Jul 29, 2021
DOI: 10.1016/j.compbiomed.2021.104686
PMID: 34340125
PMCID: PMC8319042
PubMed Central
  • Article


The main protease of SARS-CoV-2 is one of the key targets to develop and design antiviral drugs. There is no general agreement on the use of non-steroidal anti-inflammatory drugs (NSAIDs) in COVID-19. In this study, we investigated NSAIDs as potential inhibitors for chymotrypsin-like protease (3CLpro) and the main protease of the SARS-CoV-2 to find out the best candidates, which can act as potent inhibitors against the main protease. We also predicted the effect of NSAIDs on the arachidonic pathway and evaluated the hepatotoxicity of the compounds using systems biology techniques. Molecular docking was conducted via AutoDock Vina to estimate the interactions and binding affinities between selected NSAIDs and the main protease. Molecular docking results showed the presence of 10 NSAIDs based on lower binding energy (kcal/mol) toward the 3CLpro inhibition site compared to the co-crystal native ligand Inhibitor N3 (−6.6 kcal/mol). To validate the docking results, molecular dynamic (MD) simulations on the top inhibitor, Talniflumate, were performed. To obtain differentially-expressed genes under the 27 NSAIDs perturbations, we utilized the L1000 final Z-scores from the NCBI GEO repository (GSE92742). The obtained dataset included gene expression profiling signatures for 27 NSAIDs. The hepatotoxicity of NSAIDs was studied by systems biology modeling of Disturbed Metabolic Pathways. This study highlights the new application of NSAIDs as anti-viral drugs used against COVID-19. NSAIDs may also attenuate the cytokine storm through the downregulation of inflammatory mediators in the arachidonic acid pathway.

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