Coronavirus (SARS-CoV-2) Deactivation via Spike Glycoprotein Shielding by Old Drugs: Molecular Docking Approach

Document Type : Original Article


Department of Biology, Faculty of Science, Shahid Chamran University of Ahvaz, Ahvaz, Iran


Today the disease of COVID-19 comprises the most serious problem against human health worldwide with a high rate of virulence and mortality. The disease is caused by the SARS-CoV-2 virus from the beta coronavirus family. The virus makes use of its surface glycoprotein named S protein or spike to enter the human cells. The virus is attached to its receptor of angiotensin-converting enzyme 2 on the cell surface via its receptor-binding domain and fused after cleavage at S2' site that is carried out by surface protease. Vaccines or drugs interfering with S protein binding or blocking the cleavage sites of S protein could be considered as a treat to get rid of the infection. In the current work and through molecular docking and molecular dynamics experiments, 14 drugs were selected based on their molecular weights among 100 drugs to study their shielding potency toward S protein binding sites. The obtained results indicate that fidaxomicin, niclosamide, and flubendazole bind specifically to the S2' cleavage site; while ivermectin, rapamycin, heparin, azithromycin, clarithromycin, and erythromycin bind both receptor-binding domain and S2' and can prevent virus attachment to its receptor and may be useful as a prophylactic candidate for COVID-19 management after clinical approval.


Main Subjects

Abdelouahab C, Abderrahmane B. Docking Efficiency Comparison of Surflex, a Commercial Package and Arguslab, a Licensable Freeware. J Comput Sci Syst Biol 2008, 1:081-086.
Altenburg J, de Graaff CS, van der Werf TS, Boersma WG. Immunomodulatory effects of macrolide antibiotics - part 1: biological mechanisms. Respiration. 2011, 81(1):67-74.
Basu-Ray I, Almaddah NK, Adeboye A, Soos MP. Cardiac Manifestations Of Coronavirus. [Updated 2020 Aug 8]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2020 Jan-. Available from:
Bryant A, Lawrie TA, Dowswell T, Fordham EJ, Mitchell S, Hill SR, Tham TC. Ivermectin for Prevention and Treatment of COVID-19 Infection: A Systematic Review, Meta-analysis, and Trial Sequential Analysis to Inform Clinical Guidelines, American Journal of Therapeutics: 2021, 28(4):e434-e460. doi: 10.1097/MJT.0000000000001402
Caly L, Druce JD, Catton MG, Jans DA, Wagstaff KM. The FDA-approved drug ivermectin inhibits the replication of SARS-CoV-2 in vitro. Antiviral Res. 2020, 178:104787.
Chan JF, Yuan S, Kok KH, To KK, Chu H, Yang J, et al. A familial cluster of pneumonia associated with the 2019 novel coronavirus indicating person-to-person transmission: a study of a family cluster. Lancet 2020, 395(10223):514-523
Coutard B, Valle C, de Lamballerie X, Canard B, Seidah NG, et al. The spike glycoprotein of the new coronavirus SARS-CoV-2 contains a furin-like cleavage site absent in CoV of the same clade. Antiviral Res. 2020, 176:104742.
Dayer MR. Old drugs for newly emerging viral disease, COVID-19: Bioinformatic Prospective. arXiv: 2003.04524,
Dayer MR. Comparison of Newly Assembled Full Length HIV-1 Integrase With Prototype Foamy Virus Integrase: Structure-Function Prospective. Jundishapur J Microbiol. 2016, 9(5):e29773.
Dayer MR, Dayer MS. Whiskers-less HIV-protease: a possible way for HIV-1 deactivation. J Biomed Sci. 2013, 20:67
Glowacka I, Bertram S, Muller MA, Allen P, Soilleux E, Pfefferle S, et al. Evidence that TMPRSS2 activates the severe acute respiratory syndrome coronavirus Spike protein for membrane fusion and reduces viral control by the humoral immune response. J Virol 2011, 85(9):4122–4134.
Gozzo L, Viale P, Longo L, Vitale DC, Drago F. The Potential Role of Heparin in Patients With COVID-19: Beyond the Anticoagulant Effect. A Review. Front Pharmacol. 2020, 11:1307. Published 2020 Aug 21. doi:10.3389/fphar.2020.01307
Huang C, Wang Y, Li X, Ren L, Zhao J, Hu Y, et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet 395(10223):497-506.
Huang C, Xingwang L, Lili R, Jianping Z, Yi H. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. The Lancet, 2020 , 395(10223): 497-506
Iwata-Yoshikawa N, Okamura T, Shimizu Y, Hasegawa H, Takeda M, Nagata N. TMPRSS2 contributes to virus spread and immunopathology in the airways of murine models after coronavirus infection. J Virol. 2019, 93(6):e01815-18.
Leone S, Zuccoli ML, Fucile C, Storace S, Martelli A, Mattioli, F. Heparin-induced acute adverse reaction--case report of a patient with acute trauma and a genetic predisposition to thrombotic events: a concurrence of events. J Clin Pharm Ther. 2012, 37(6):733-5.
Lu L, Liu Q, Zhu Y, Chan KH, Qin L, Li Y, et al. Structure-based discovery of Middle East respiratory syndrome coronavirus fusion inhibitor. Nat. Commun. 2014, 5:3067.
Lu R, Zhao X, Li J, Niu P, Yang B, Wu H, et al. Genomic characterisation and epidemiology of 2019 novel coronavirus: implications for virus origins and receptor binding. Lancet 2020, 395(10224):565-574.
Macindoe G, Mavridis L, Venkatraman V, Devignes MD, Ritchie DW. HexServer: an FFT-based protein docking server powered by graphics processors. Nucleic Acids Res. 2010, 38-9
Mastrangelo E, Pezzullo M, De Burghgraeve T, Kaptein S, Pastorino B, Dallmeier K, et al. Ivermectin is a potent inhibitor of flavivirus replication specifically targeting NS3 helicase activity: new prospects for an old drug. J Antimicrob Chemother. 2012 Aug;67(8):1884-94.
Ohe M, Shida H, Jodo S, Kusunoki Y, Seki M, Furuya K, et al. Macrolide treatment for COVID-19: Will this be the way forward? Biosci Trends. 2020 May 21;14(2):159-160. Epub 2020 Apr 5. PMID: 32249257.
Pallesen J, Wang N, Corbett KS, Wrapp D, Kirchdoerfer RN, Turner HL, et al. Proc. Natl. Acad. Sci. U.S.A. 2017, 114(35), E7348–E7357.
Parvez MSA, Karim MA, Hasan M, Jaman J, Karim Z, Tahsin T, Hasan MN, Hosen MJ. Prediction of potential inhibitors for RNA-dependent RNA polymerase of SARS-CoV-2 using comprehensive drug repurposing and molecular docking approach. Int J Biol Macromol. 2020 Nov 15;163:1787-1797. doi: 10.1016/j.ijbiomac.2020.09.098. Epub 2020 Sep 17. PMID: 32950529; PMCID: PMC7495146.
Riffo-Vasquez Y, Somani A, Man F, Amison R, Pitchford S, Page CP. A non-anticoagulant fraction of heparin inhibits leukocyte diapedesis into the lung by an effect on platelets. Am J Respir Cell Mol Biol 2016, 55:554-563.
Ritchie DW, Kozakov D, Vajda S. Accelerating Protein-Protein Docking Correlations Using A Six-Dimensional Analytic FFT Generating Function, Bioinformatics 2008, 24(17), 1865-1873
Romanelli A, Mascolo S, Sirolimus to treat SARS-CoV-2 infection: an old drug for a new disease  J Res Clin Med, 2020, 8: 44
Song W, Gui M, Wang X, Xiang Y. Cryo-EM structure of the SARS-COVcoronavirus spike glycoprotein in complex with its host cell receptor ACE2. PLoS Pathog 2018, 14(8): e1007236.
Spiezia L, Boscolo A, Poletto F, Cerruti L, Tiberio I, Campello E, et al. COVID-19-Related Severe Hypercoagulability in Patients Admitted to Intensive Care Unit for Acute Respiratory Failure. Thromb Haemost. 2020;120(6):998-1000.
Tang N, Bai H, Chen X, Gong J, Li D, Sun Z. Anticoagulant treatment is associated with decreased mortality in severe coronavirus disease 2019 patients with coagulopathy. J Thromb Haemost. 2020 https://doi:10.1111/jth.14817 [Epub ahead of print]
Walls AC, Xiong X, Park YJ, Tortorici MA, Snijder J, Quispe J, et al. Unexpected Receptor Functional Mimicry Elucidates Activation of Coronavirus Fusion. Cell 2019, 176(5), 1026–1039.e15.
Wrapp D, Wang N, Corbett KS, Goldsmith JA, Hsieh CL, Abiona O, et al. Cryo-EM structure of the SARS-CoV-2 spike in the prefusion conformation. Science 2020, 367:1260–1263
Wu F, Zhao S, Yu B, Chen YM, Wang W, Song ZG, et al. A new coronavirus associated with human respiratory disease in China. Nature 2020, 579(7798):265-269.
Xia S, Yan L, Xu W, Agrawal AS, Algaissi A, Tseng CK, et al. A pan-coronavirus fusion inhibitor targeting the HR1 domain of human coronavirus spike. Sci. Adv. 2019, 5(4):eaav4580 (2019).
Xia S, Zhu Y, Liu M, Lan Q, Xu W, Wu Y, et al. Fusion mechanism of SARS-CoV-2 and fusion inhibitors targeting HR1 domain in spike protein. Cell Mol Immunol. 2020 [Epub ahead of print]
Xu J, Shi PY, Li H, Zhou J. Broad Spectrum Antiviral Agent Niclosamide and Its Therapeutic Potential. ACS Infect Dis. 2020; 6(5):909-915.
Zhang L, Yan X, Fan Q, et al. D-dimer levels on admission to predict in-hospital mortality in patients with Covid-19. Journal of Thrombosis and Haemostasis : JTH. 2020 Jun;18(6):1324-1329.
Zhou P, Yang XL, Wang XG, Hu B, Zhang L, Zhang W, et al. A pneumonia outbreak associated with a new coronavirus of probable bat origin. Nature 2020, 579(7798):270-273.
Zimmermann P, Ziesenitz VC, Curtis N, Ritz N. The Immunomodulatory Effects of Macrolides-A Systematic Review of the Underlying Mechanisms. Front Immunol, 2018, 9, 302.