Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2021 Jun 21;26(12):3772.
doi: 10.3390/molecules26123772.

Computational Insights on the Potential of Some NSAIDs for Treating COVID-19: Priority Set and Lead Optimization

Ayman Abo Elmaaty  1 , Mohammed I A Hamed  2 , Muhammad I Ismail  3 , Eslam B Elkaeed  4   5 , Hamada S Abulkhair  5   6 , Muhammad Khattab  7 , Ahmed A Al-Karmalawy  6
Affiliations

Computational Insights on the Potential of Some NSAIDs for Treating COVID-19: Priority Set and Lead Optimization

Ayman Abo Elmaaty et al. Molecules. .

Abstract

The discovery of drugs capable of inhibiting SARS-CoV-2 is a priority for human beings due to the severity of the global health pandemic caused by COVID-19. To this end, repurposing of FDA-approved drugs such as NSAIDs against COVID-19 can provide therapeutic alternatives that could be utilized as an effective safe treatment for COVID-19. The anti-inflammatory activity of NSAIDs is also advantageous in the treatment of COVID-19, as it was found that SARS-CoV-2 is responsible for provoking inflammatory cytokine storms resulting in lung damage. In this study, 40 FDA-approved NSAIDs were evaluated through molecular docking against the main protease of SARS-CoV-2. Among the tested compounds, sulfinpyrazone 2, indomethacin 3, and auranofin 4 were proposed as potential antagonists of COVID-19 main protease. Molecular dynamics simulations were also carried out for the most promising members of the screened NSAID candidates (2, 3, and 4) to unravel the dynamic properties of NSAIDs at the target receptor. The conducted quantum mechanical study revealed that the hybrid functional B3PW91 provides a good description of the spatial parameters of auranofin 4. Interestingly, a promising structure-activity relationship (SAR) was concluded from our study that could help in the future design of potential SARS-CoV-2 main protease inhibitors with expected anti-inflammatory effects as well. NSAIDs may be used by medicinal chemists as lead compounds for the development of potent SARS-CoV-2 (Mpro) inhibitors. In addition, some NSAIDs can be selectively designated for treatment of inflammation resulting from COVID-19.

Keywords: DFT calculations; SARS-CoV-2 main protease; docking; drug repurposing; molecular dynamics.

PubMed Disclaimer

Figures

Figure 1
Figure 1
Inflammatory cytokine storm induced by SARS-CoV-2 infections and the role of anti-inflammatory drugs such as NSAIDs.
Figure 2
Figure 2
Chemical structures (in descending order of their docking scores): N3 1, Sulfinpyrazone 2, Indomethacin 3, Auranofin 4, Phenylbutazone 5, Celecoxib 6, sulfasalazine 7, Oxyphenbutazone 8, Sulindac 9, Metamizole 10, Meloxicam 11, Oxaprozin 12, Nimesulide 13, Piroxicam 14, Valdecoxib 15, Zomepirac 16, Rofecoxib 17, Etodolac 18, Tenoxicam 19, Carprofen 20, Ketoprofen 21, Tolmetin 22, Nabumetone 23, Probenecid 24, Ketorolac 25, Ibuprofen 26, Fenoprofen 27, Flurbiprofen 28, Salsalate 29, Naproxen 30, Flufenamic acid 31, Mefenamic acid 32, Diclofenac 33, Meclofenamic acid 34, Phenacetin 35, Diflunisal 36, Aurothioglucose 37, Aspirin 38, Sodium aurothiomalate 39, Paracetamol 40, and Allopurinol 41.
Figure 3
Figure 3
(A) RMSD (Root Mean Square Deviation) of the protein during the simulation time. (B) Per residue RMSF (Root Mean Square Fluctuation) of the protein amino acids. (C) RMSD of the docked poses of the four ligands inside the protein binding site. (Green: N3, Blue: Sulfinpyrazone, Yellow: Indomethacin, Red: Auranofin.)
Figure 4
Figure 4
The aligned structures of protein–ligand complexes for sulfinpyrazone (A), indomethacin (B), and auranofin (C) during simulation. (White: 0 ns, yellow: 75 ns, blue: 150 ns.)
Figure 4
Figure 4
The aligned structures of protein–ligand complexes for sulfinpyrazone (A), indomethacin (B), and auranofin (C) during simulation. (White: 0 ns, yellow: 75 ns, blue: 150 ns.)
Figure 5
Figure 5
Number of hydrogen bonds formed between each ligand and the protein during the simulation.
Figure 6
Figure 6
Protein–ligand contacts histograms for sulfinpyrazone (A), indomethacin (B), auranofin (C), and N3 (D).
Figure 6
Figure 6
Protein–ligand contacts histograms for sulfinpyrazone (A), indomethacin (B), auranofin (C), and N3 (D).
Figure 6
Figure 6
Protein–ligand contacts histograms for sulfinpyrazone (A), indomethacin (B), auranofin (C), and N3 (D).
Figure 7
Figure 7
Heat map representing the number of protein–ligand contacts for sulfinpyrazone (A), indomethacin (B), auranofin (C), and N3 (D).
Figure 7
Figure 7
Heat map representing the number of protein–ligand contacts for sulfinpyrazone (A), indomethacin (B), auranofin (C), and N3 (D).
Figure 7
Figure 7
Heat map representing the number of protein–ligand contacts for sulfinpyrazone (A), indomethacin (B), auranofin (C), and N3 (D).
Figure 7
Figure 7
Heat map representing the number of protein–ligand contacts for sulfinpyrazone (A), indomethacin (B), auranofin (C), and N3 (D).
Figure 8
Figure 8
Electron density distribution of the molecular electrostatic potential (MEP) map and the outermost molecular orbitals of auranofin computed using different hybrid functionals in combination with def2tzvp and 6-311++G** basis sets.
Figure 9
Figure 9
Computed electronic circular dichroism (ECD) of auranofin computed using different hybrid functionals in combination with def2tzvp and 6-311++G** basis sets.
Figure 10
Figure 10
Structure-Activity Relationship (SAR) studies of the studied FDA-approved NSAIDs (2-41) according to their binding potentials towards the SARS-CoV-2 Mpro.*: The connection point to the main molecule.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. WHO Coronavirus Disease (COVID-19) Pandemic. [(accessed on 11 April 2021)];2021 Available online: https://www.who.int/emergencies/diseases/novel-coronavirus-2019?gclid=Cj....
    1. Worldometer Coronavirus. [(accessed on 11 April 2021)];2021 Available online: https://www.worldometers.info/coronavirus/?utm_campaign=homeAdvegas1?
    1. Chen J., Wang Y.K., Gao Y., Hu L.S., Yang J.W., Wang J.R., Sun W.J., Liang Z.Q., Cao Y.M., Cao Y.B. Protection against COVID-19 injury by qingfei paidu decoction via anti-viral, anti-inflammatory activity and metabolic programming. Biomed. Pharmacother. 2020;129:110281. doi: 10.1016/j.biopha.2020.110281. - DOI - PMC - PubMed
    1. Sarhan A.A., Ashour N.A., Al-Karmalawy A.A. The journey of antimalarial drugs against SARS-CoV-2: Review article. Inform. Med. Unlocked. 2021;24:100604. doi: 10.1016/j.imu.2021.100604. - DOI - PMC - PubMed
    1. Pushpakom S., Iorio F., Eyers P.A., Escott K.J., Hopper S., Wells A., Doig A., Guilliams T., Latimer J., McNamee C. Drug repurposing: Progress, challenges and recommendations. Nat. Rev. Drug Dis. 2019;18:41–58. doi: 10.1038/nrd.2018.168. - DOI - PubMed

MeSH terms

LinkOut - more resources

-