Aim: SARS-CoV-2, an emerging betacoronavirus, is the causative agent of COVID-19. Currently, there are few specific and selective antiviral drugs for the treatment and vaccines to prevent contagion. However, their long-term effects can be revealed after several years, and new drugs for COVID-19 should continue to be investigated. Materials & methods: In the first step of our study we identified, through a gene expression analysis, several drugs that could act on the biological pathways altered in COVID-19. In the second step, we performed a docking simulation to test the properties of the identified drugs to target SARS-CoV-2. Results: The drugs that showed a higher binding affinity are bardoxolone (-8.78 kcal/mol), irinotecan (-8.40 kcal/mol) and pyrotinib (-8.40 kcal/mol). Conclusion: We suggested some drugs that could be efficient in treating COVID-19.

Keywords:

References

1. Hall DC Jr, Ji HF. A search for medications to treat COVID-19 via in silico molecular docking models of the SARS-CoV-2 spike glycoprotein and 3CL protease. Travel. Med. Infect. Dis. 35, 101646 (2020).
MedlineGoogle Scholar
2. Han DP, Penn-Nicholson A, Cho MW. Identification of critical determinants on ACE2 for SARS-CoV entry and development of a potent entry inhibitor. Virology 350(1), 15–25 (2006).
Medline CASGoogle Scholar
3. Brown JD. Antihypertensive drugs and risk of COVID-19? Lancet Respir. Med. 8(5), e28 (2020).
Medline CASGoogle Scholar
4. Lu IL, Mahindroo N, Liang PH et al. Structure-based drug design and structural biology study of novel nonpeptide inhibitors of severe acute respiratory syndrome coronavirus main protease. J. Med. Chem. 49(17), 5154–5161 (2006).
Medline CASGoogle Scholar
5. Blanchard JE, Elowe NH, Huitema C et al. High-throughput screening identifies inhibitors of the SARS coronavirus main proteinase. Chem. Biol. 11(10), 1445–1453 (2004).
Medline CASGoogle Scholar
6. Zhang L, Lin D, Sun X et al. Crystal structure of SARS-CoV-2 main protease provides a basis for design of improved α-ketoamide inhibitors. Science 368(6489), 409–412 (2020).
Medline CASGoogle Scholar
7. Jin Z, Du X, Xu Y et al. Structure of M^pro from SARS-CoV-2 and discovery of its inhibitors. Nature 582(7811), 289–293 (2020).
Medline CASGoogle Scholar
8. Cava C, Bertoli G, Castiglioni I. In silico discovery of candidate drugs against COVID-19. Viruses 12(4), 404 (2020).
CASGoogle Scholar
9. Cheng F, Murray JL, Rubin DH. Drug repurposing: new treatments for Zika virus infection? Trends Mol. Med. 22, 919–921 (2016).
MedlineGoogle Scholar
10. Cheng F, Murray JL, Zhao J, Sheng J, Zhao Z, Rubin DH. Systems biology-based investigation of cellular antiviral drug targets identified by gene-trap insertional mutagenesis. PLoS Comput. Biol. 12, e1005074 (2016).
MedlineGoogle Scholar
11. Mustafa S, Balkhy H, Gabere M. Peptide–protein interaction studies of antimicrobial peptides targeting middle east respiratory syndrome coronavirus spike protein: an in silico approach. Adv. Bioinform. 2019, doi: 10.1155/2019/6815105 (2019).
Google Scholar
12. Lionta E, Spyrou G, Vassilatis DK, Cournia Z. Structure-based virtual screening for drug discovery: principles, applications and recent advances. Curr. Top. Med. Chem. 14, 1923–1938 (2014).
Medline CASGoogle Scholar
13. Cheng LS, Amaro RE, Xu D, Li WW, Arzberger PW, McCammon JA. Ensemble-based virtual screening reveals potential novel antiviral compounds for avian influenza neuraminidase. J. Med. Chem. 51, 3878–3894 (2008).
Medline CASGoogle Scholar
14. Zhang L, Ai HX, Li SM et al. Virtual screening approach to identifying influenza virus neuraminidase inhibitors using molecular docking combined with machine-learning-based scoring function. Oncotarget 8(47), 83142–83154 (2017).
MedlineGoogle Scholar
15. Shah B, Modi P, Sagar SR. In silico studies on therapeutic agents for COVID-19: drug repurposing approach. Life Sci. 252, 117652 (2020).
Medline CASGoogle Scholar
16. Aatif M, Muteeb G, Alsultan A, Alshoaibi A, Khelif BY. Dieckol and its derivatives as potential inhibitors of SARS-CoV-2 spike protein (UK strain: VUI 202012/01): a computational study. Mar. Drugs 19(5), 242 (2021).
Medline CASGoogle Scholar
17. Prabhu D, Rajamanikandan S, Sureshan M, Jeyakanthan J, Saraboji K. modeling studies reveal the importance of the C-terminal inter motif loop of NSP1 as a promising target site for drug discovery and screening of potential phytochemicals to combat SARS-CoV-2. J. Mol. Graph. Model. 106, 107920 (2021).
Medline CASGoogle Scholar
18. Vivek-Ananth RP, Rana A, Rajan N, Biswal HS, Samal A. In silico identification of potential natural product inhibitors of human proteases key to SARS-CoV-2 infection. Molecules 25(17), 3822 (2020).
CASGoogle Scholar
19. Gentile F, Agrawal V, Hsing M et al. Deep docking: a deep learning platform for augmentation of structure based drug discovery. ACS Cent. Sci. 6(6), 939–949 (2020).
Medline CASGoogle Scholar
20. Nguyen DD, Gao K, Chen J, Wang R, Wei GW. Potentially highly potent drugs for 2019-nCoV. Biorxiv doi: https://doi.org/10.1101/2020.02.05.936013 (2020).
Google Scholar
21. Salmaso V, Moro S. Bridging molecular docking to molecular dynamics in exploring ligand-protein recognition process: an overview. Front. Pharmacol. 9, 923 (2018).
MedlineGoogle Scholar
22. Colaprico A, Silva TC, Olsen C et al. TCGAbiolinks: an R/Bioconductor package for integrative analysis of TCGA data. Nucleic Acids Res. 44(8), e71 (2016).
MedlineGoogle Scholar
23. Günther S, Kuhn M, Dunkel M et al. SuperTarget and Matador: resources for exploring drug-target relationships. Nucleic Acids Res. 36(Database issue), D919–D922 (2008).
Medline CASGoogle Scholar
24. Cotto KC, Wagner AH, Feng YY et al. DGIdb 3.0: a redesign and expansion of the drug-gene interaction database. Nucleic Acids Res. 46(D1), D1068–D1073 (2018).
Medline CASGoogle Scholar
25. Benjamini Y, Hochberg Y. Controlling the false discovery rate: a practical and powerful approach to multiple testing. J. R. Stat. Soc. Ser. B Methodol. 57, 289–300 (1995).
Google Scholar
26. Morris GM, Huey R, Lindstrom W et al. AutoDock4 and AutoDockTools4: automated docking with selective receptor flexibility. J. Comput. Chem. 30(16), 2785–2791 (2009).
Medline CASGoogle Scholar
27. Kim S, Chen J, Cheng T et al. PubChem 2019 update: improved access to chemical data. Nucleic Acids Res. 47(D1), D1102–D1109 (2019).
MedlineGoogle Scholar
28. Dassault Systèmes. BIOVIA, Discovery Studio Modeling Environment, release. (2020). https://www.3ds.com/products-services/biovia/products/molecular-modeling-simulation/biovia-discovery-studio/
Google Scholar
29. Salentin S, Schreiber S, Haupt VJ, Adasme MF, Schroeder M. PLIP: fully automated protein–ligand interaction profiler. Nucleic Acids Res. 43(W1), W443–447 (2015).
Medline CASGoogle Scholar
30. Daina A, Michielin O, Zoete V. SwissADME: a free web tool to evaluate pharmacokinetics, drug-likeness and medicinal chemistry friendliness of small molecules. Sci. Rep. 7, 42717 (2017).
MedlineGoogle Scholar
31. Hastings J, Owen G, Dekker A et al. ChEBI in 2016: improved services and an expanding collection of metabolites. Nucleic Acids Res. 44(D1), D1214–D1219 (2016).
Medline CASGoogle Scholar
32. Gentile P, Sterodimas A, Pizzicannella J, Calabrese C, Garcovich S. Research progress on mesenchymal stem cells (MSCs), adipose-derived mesenchymal stem cells (AD-MSCs), drugs, and vaccines in inhibiting COVID-19 disease. Aging Dis. 11(5), 1191–1201 (2020).
Medline CASGoogle Scholar
33. Gentile P, Sterodimas A. Adipose stem cells (ASCs) and stromal vascular fraction (SVF) as a potential therapy in combating (COVID-19)-disease. Aging Dis. 11(3), 465–469 (2020).
MedlineGoogle Scholar
34. Gentile P, Sterodimas A. Adipose-derived stromal stem cells (ASCs) as a new regenerative immediate therapy combating coronavirus (COVID-19)-induced pneumonia. Expert Opin. Biol. Ther. 20(7), 711–716 (2020).
Medline CASGoogle Scholar
35. Durand N, Mallea J, Zubair AC. Insights into the use of mesenchymal stem cells in COVID-19 mediated acute respiratory failure. NPJ Regen. Med. 5(1), 17 (2020).
Medline CASGoogle Scholar
36. Rad F, Ghorbani M, Mohammadi Roushandeh A, Habibi Roudkenar M. Mesenchymal stem cell-based therapy for autoimmune diseases: emerging roles of extracellular vesicles. Mol. Biol. Rep. 46(1), 1533–1549 (2019).
Medline CASGoogle Scholar
37. Food and Drug Administration. Emergency Use Authorization. https://www.fda.gov/emergency-preparedness-and-response/mcm-legal-regulatory-and-policy-framework/emergency-use-authorization#coviddrugs
Google Scholar
38. Gordon CJ, Tchesnokov EP, Feng JY, Porter DP, Götte M. The antiviral compound remdesivir potently inhibits RNA-dependent RNA polymerase from Middle East respiratory syndrome coronavirus. J. Biol. Chem. 295(15), 4773–4779 (2020).
Medline CASGoogle Scholar
39. Ledford H. COVID antibody treatments show promise for preventing severe disease. Nature 591(7851), 513–514 (2021).
Medline CASGoogle Scholar
40. Huang DT, McCreary EK, Bariola JR et al. The UPMC OPTIMISE-C19 (optimizing treatment and impact of monoclonal antibodies through evaluation for COVID-19) trial: a structured summary of a study protocol for an open-label, pragmatic, comparative effectiveness platform trial with response-adaptive randomization. Trials 22(1), 363 (2021).
Medline CASGoogle Scholar
41. Hansen J, Baum A, Pascal KE et al. Studies in humanized mice and convalescent humans yield a SARS-CoV-2 antibody cocktail. Science 369(6506), 1010–1014 (2020).
Medline CASGoogle Scholar
42. Devarasetti PK, Rajasekhar L, Baisya R, Sreejitha KS, Vardhan YK. A review of COVID-19 convalescent plasma use in COVID-19 with focus on proof of efficacy. Immunol. Res. 69(1), 18–25 (2021).
Medline CASGoogle Scholar
43. Naqvi AAT, Fatima K, Mohammad T et al. Insights into SARS-CoV-2 genome, structure, evolution, pathogenesis and therapies: structural genomics approach. Biochim. Biophys. Acta. Mol. Basis Dis. 1866(10), 165878 (2020).
Medline CASGoogle Scholar
44. Klemm T, Ebert G, Calleja DJ et al. Mechanism and inhibition of the papain-like protease, PL^pro, of SARS-CoV-2. EMBO J. 39(18), e106275 (2020).
Medline CASGoogle Scholar
45. Bepari AK, Reza HM. Identification of a novel inhibitor of SARS-CoV-2 3CL-PRO through virtual screening and molecular dynamics simulation. Peer J. 9, e11261 (2021).
MedlineGoogle Scholar
46. Nio Y, Sasai M, Akahori Y et al. Bardoxolone methyl as a novel potent antiviral agent against hepatitis B and C viruses in human hepatocyte cell culture systems. Antiviral Res. 169, 104537 (2019).
Medline CASGoogle Scholar
47. Wyler E, Franke V, Menegatti J et al. Single-cell RNA-sequencing of herpes simplex virus 1-infected cells connects NRF2 activation to an antiviral program. Nat. Commun. 10(1), 4878 (2019).
MedlineGoogle Scholar
48. Patra U, Mukhopadhyay U, Sarkar R, Mukherjee A, Chawla-Sarkar M. RA-839, a selective agonist of Nrf2/ARE pathway, exerts potent anti-rotaviral efficacy in vitro. Antiviral Res. 161, 53–62 (2019).
Medline CASGoogle Scholar
49. Kulu Y, Kawasaki H, Donahue JM et al. Concurrent chemotherapy inhibits herpes simplex virus-1 replication and oncolysis. Cancer Gene Ther. 20(2), 133–140 (2013).
Medline CASGoogle Scholar
50. Lipid Nanocarriers for Drug Targeting Grumezescu AM (Ed.). William Andrew (2018).
Google Scholar
51. Lui LCY, Chan RTT, Kwok CCH et al. Reactivation of hepatitis B after irinotecan. J. Hong Kong College of Radiologists 7(2), 72 (2004).
Google Scholar
52. Gourd E. Pyrotinib shows activity in metastatic breast cancer. Lancet Oncol. 18(11), e643 (2017).
MedlineGoogle Scholar
53. Sisk JM, Frieman MB, Machamer CE. Coronavirus S protein-induced fusion is blocked prior to hemifusion by Abl kinase inhibitors. J. Gen. Virol. 99(5), 619–630 (2018).
Medline CASGoogle Scholar
54. Curtin N, Bányai K, Thaventhiran J, Le Quesne J, Helyes Z, Bai P. Repositioning PARP inhibitors for SARS-CoV-2 infection(COVID-19); a new multi-pronged therapy for acute respiratory distress syndrome? Br. J. Pharmacol. 177(16), 3635–3645 (2020).
Medline CASGoogle Scholar
55. Morrow DA, Brickman CM, Murphy SA et al. A randomized, placebo-controlled trial to evaluate the tolerability, safety, pharmacokinetics, and pharmacodynamics of a potent inhibitor of poly(ADP-ribose) polymerase (INO-1001) in patients with ST-elevation myocardial infarction undergoing primary percutaneous coronary intervention: results of the TIMI 37 trial. J. Thromb. Thrombolysis. 27(4), 359–364 (2009).
Medline CASGoogle Scholar
56. Sabetian S, Castiglioni I, Jahromi BN, Mousavi P, Cava C. In silico identification of miRNA-lncRNA interactions in male reproductive disorder associated with COVID-19 infection. Cells. 10(6), 1480 (2021).
MedlineGoogle Scholar
57. Cava C, Bertoli G, Castiglioni I. A protein interaction map identifies existing drugs targeting SARS-CoV-2. BMC Pharmacol Toxicol. 21(1), 65 (2020).
Medline CASGoogle Scholar

Vol. 16, No. 8

Supplemental Materials

Metrics

Downloaded 2,084 times

History

Received 27 November 2020

Accepted 30 June 2021

Published online 20 July 2021

Published in print August 2021

Information

Keywords

Supplementary data

To view the supplementary data that accompany this paper please visit the journal website at: www.futuremedicine.com/doi/suppl/10.2217/fvl-2020-0392

Author contributions

C Cava has made substantial contribution to the acquisition, analysis and interpretation of data. G Bertoli has made substantial contribution to the interpretation of data. I Castiglioni revised the manuscript.

Acknowledgments

IBFM-CNR thanks the generous support from Dassault Systèmes BIOVIA for the use of BIOVIA Discovery Studio Academic Research Suite in this work.

Financial & competing interests disclosure

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript.

PDF download