AccScience Publishing / ITPS / Volume 7 / Issue 2 / DOI: 10.36922/itps.1651
ORIGINAL RESEARCH ARTICLE

Evaluating the SARS-CoV-2 spike glycoprotein as a molecular target for therapeutic development

Brandon H. Adame-Velasco1† Pablo Octavio-Aguilar1* Luis H. Mendoza-Huizar2† Liliana M. Aguilar-Castro1†
Show Less
1 Genetics Laboratory, Biological Research Center, Autonomous University of the State of Hidalgo, Mineral de la Reforma, Hidalgo, Mexico
2 Academic Area of Chemistry, Autonomous University of the State of Hidalgo, Mineral de la Reforma, Hidalgo, Mexico
INNOSC Theranostics and Pharmacological Sciences 2024, 7(2), 1651 https://doi.org/10.36922/itps.1651
Submitted: 22 August 2023 | Accepted: 4 December 2023 | Published: 26 March 2024
© 2024 by the Author (s). This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution -Noncommercial 4.0 International License (CC-by the license) ( https://creativecommons.org/licenses/by-nc/4.0/ )
Abstract

The SARS-CoV-2 virus gains entry into host cells by binding its spike glycoprotein (S-glycoprotein) to the angiotensin 2 receptor. This viral protein contains several conserved regions, such as the receptor binding domain region, making it an ideal target for treating COVID-19. Notably, the majority of existing vaccines elicit antigenic reaction by targeting this protein epitope. This study evaluated the binding affinities of 44 different drugs against the SARS-CoV-2 S-glycoprotein, considering their toxicity profiles and previous clinical studies at different testing stages. Our results revealed that maraviroc and estradiol benzoate exhibited high affinities (−7.7 and −7.6 kcal mol−1, respectively), while other ligands, such as indinavir and ritonavir, showed affinity at lower levels. Among the drugs with high affinity, toxicity levels ranged from harmful if swallowed (300 mg/kg < LD50 < 2000 mg/kg) to non-toxic (LD50 > 5000 mg/kg), with only three having undergone clinical testing, yielding promising or controversial results. Furthermore, emtricitabine and docosanol, previously explored as COVID-19 treatments, exhibited the lowest affinities (−4.7 and −3.9 kcal mol−1, respectively), with associated harmful effects if swallowed. These results provide essential information about drug interaction against the SARS-CoV-2 S-glycoprotein and potential treatment pathways for COVID-19.

Keywords
SARS-CoV-2
Coronavirus spike glycoprotein
Molecular docking simulation
Pharmacology
Cluster MCMC
Funding
None.
References
  1. Escudero S, Guarner J, Galindo-Fraga A, Escudero- Salamanca M, Alcocer-Gamba M, Rio CD. The SARS-CoV-2 coronavirus pandemic (COVID-19): Current situation and implications for Mexico. Arch Cardiol Méx. 2020;90(Supl 1):7-14. doi: 10.24875/acm.m20000064

 

  1. Li F. Structure, function, and evolution of coronavirus spike proteins. Annu Rev Virol. 2016;3(1):237-261. doi: 10.1146/annurev-virology-110615-042301

 

  1. Gui M, Song W, Zhou H, et al. Cryo-electron microscopy structures of the SARS-CoV spike glycoprotein reveal a prerequisite conformational state for receptor binding. Cell Res. 2016;27:119-129. doi: 10.1038/cr.2016.152

 

  1. Tolentino-Mendoza ME, Octavio-Aguilar P. Historia natural de los coronavirus y el desarrollo de vacunas. Herreriana. 2023;4(2):43-50. doi: 10.29057/h.v5i1.8592

 

  1. Accinelli RA, Zhang-Xu CM, Ju-Wang JD, et al. COVID-19: The pandemic due to the new SARS-CoV-2 virus. Rev Peru Med Exp Public Health. 2020;37(2):302-311. doi: 10.17843/rpmesp.2020.372.5411

 

  1. Letko M, Marzi A, Munster V. Functional assessment of cell entry and receptor usage for SARS-CoV-2 and other lineage B betacoronaviruses. Nat Microbiol. 2020;5:562-569. doi: 10.1038/s41564-020-0688-y

 

  1. Kullappan M, Mary U, Ambrose JM, Veeraghavan VP, Surapaneni KM. Elucidating the role of N440K mutation in SARS-CoV-2 spike-ACE-2 binding affinity and COVID-19 severity by virtual screening, molecular docking and dynamics approach. J Biomol Struct Dyn. 2023;41(3):912-926. doi: 10.1080/07391102.2021.2014973

 

  1. Abeywardhana S, Premathilaka M, Bandaranayake U, Perera D. In silico study of SARS-CoV-2 spike protein RBD and human ACE-2 affinity dynamics across variants and Omicron subvariants. J Med Virol. 2023;95(1):e28406. doi: 10.1002/jmv.28406

 

  1. Jayk AB, Gomes da Silva MM, Musungaie DB, et al. Molnupiravir for oral treatment of covid-19 in nonhospitalized patients. N Engl J Med. 2022;386(6):509-520. doi: 10.1056/NEJMoa2116044

 

  1. Wang M, Cao R, Zhang L, et al. Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro. Cell Res. 2020;30(3):269-271. doi: 10.1038/s41422-020-0282-0

 

  1. Goldman JD, Lye DCB, Hui DS, et al. Remdesivir for 5 or 10 Days in patients with severe covid-19. N Engl J Med. 2020;383(19):1827-1837. doi: 10.1056/NEJMoa2015301

 

  1. López-Medina E, López P, Hurtado IC, et al. Effect of ivermectin on time to resolution of symptoms among adults with mild COVID-19: A Randomized clinical trial. JAMA. 2021;325(14):1426-1435. doi: 10.1001/jama.2021.3071

 

  1. Pirolli D, Righino B, Camponeschi C, Ria F, Di Sante G, De Rosa MC. Virtual screening and molecular dynamics simulations provide insight into repurposing drugs against SARS-CoV-2 variants Spike protein/ACE2 interface. Sci Rep. 2023;13:1494. doi: 10.1038/s41598-023-28716-8

 

  1. Takashita E, Yamayoshi S, Simon V, et al. Efficacy of antibodies and antiviral drugs against Omicron BA.2.12.1, BA.4, and BA.5 subvariants. N Engl J Med. 2022;387(5):468-470. doi: 10.1056/NEJMc2207519

 

  1. Wrapp D, Wang N, Corbett KS, et al. Prefusion 2019-nCoV spike glycoprotein with a single receptor-binding domain up. Science. 2020;367(6483):1260-1263. doi: 10.1126/science.abb2507

 

  1. Pettersen EF, Goddard TD, Huang CC, et al. UCSF Chimera--a visualization system for exploratory research and analysis. J Comput Chem. 2004;25(13):1605-1612. doi: 10.1002/jcc.20084

 

  1. Waterhouse A, Bertoni M, Bienert S, et al. SWISS-MODEL: Homology modelling of protein structures and complexes. Nucleic Acids Res. 2018;46:W296-W303. doi: 10.1093/nar/gky427

 

  1. Banerjee P, Eckert OA, Schrey AK, Preissner R. ProTox-II: A webserver for the prediction of toxicity of chemicals. Nucleic Acids Res. 2018;2:W257-W263. doi: 10.1093/nar/gky318

 

  1. Burley SK, Bhikadiya C, Bi C, et al. RCSB Protein Data Bank (RCSB.org): Delivery of experimentally-determined PDB structures alongside one million computed structure models of proteins from artificial intelligence/machine learning. Nucleic Acids Res. 2023;51(6):D488-D508. doi: 10.1093/nar/gkac1077

 

  1. Dallakyan S, Olson AJ. Small-molecule library screening by docking with pyrx. Methods Mol Biol. 2015;1263:243-250. doi: 10.1007/978-1-4939-2269-7_19

 

  1. Hammer O, Harper DAT, Ryan PD. PAST: Paleontological statistics software package for education and data analysis. Paleontol Electron. 2001;4(1):9.

 

  1. Zafari ZF, Sarmast SM. Estradiol and COVID-19: Does 17-estradiol have an immune-protective function in women against coronavirus? J Family Reprod Health. 2021;15(3):150-159. doi: 10.18502/jfrh.v15i3.7132

 

  1. Piplani S, Singh P, Petrovsky N, Winkler DA. Identifying SARS-CoV-2 drugs binding to the spike fatty acid binding pocket using in silico docking and molecular dynamics. Int J Mol Sci. 2023;24(4):4192. doi: 10.3390/ijms24044192

 

  1. Gupta Y, Savytskyi OV, Coban M, et al. Protein structure-based in-silico approaches to drug discovery: Guide to COVID-19 therapeutics. Mol Aspects Med. 2023;91:101151. doi: 10.1016/j.mam.2022.101151

 

  1. Yang C, Pan X, Huang Y, et al. Drug repurposing of itraconazole and estradiol benzoate against COVID-19 by blocking SARS-CoV-2 spike protein-mediated membrane fusion. Adv Ther (Weinh). 2021;4(5):2000224. doi: 10.1002/ADTP.202000224

 

  1. Tsegay KB, Adetemi CM, Gniffke EP, Sather DN, Walker JK, Smith SEP. A repurposed drug screen identifies compounds that inhibit the binding of the COVID-19 spike protein to ACE2. Front Pharmacol. 2021;12:685308. doi: 10.3389/fphar.2021.685308

 

  1. Liesenborghs L, Spriet I, Jockmans D, et al. Itraconazole for COVID-19: Preclinical studies and a proof-of-concept randomized clinical trial. EBioMedicine. 2021;66:103288. doi: 10.1016/j.ebiom.2021.103288

 

  1. Van Damme E, De Meyer S, Bojkova D, et al. In vitro activity of itraconazole against SARS-CoV-2. J Med Virol. 2021;93(7):4454-4460. doi: 10.1002/jmv.26917

 

  1. Guilck RM, Su Z, Flexner C, et al. Phase 2 study of the safety and efficacy of Vicriviroc, a CCR5 inhibitor, in HIV- 1-infected, treatment-experienced patients: AIDS clinical trials group 5211. J Infect Dis. 2007;196(2):304-312. doi: 10.1086/518797

 

  1. Cuesta-Llavona E, Gómez J, Albaiceta GM, et al. Variant-genetic and transcript-expression analysis showed a role for the chemokine-receptor CCR5 in COVID-19 severity. Int Immunopharmacol. 2021;98:107825. doi: 10.1016/J.INTIMP.2021.107825

 

  1. Risner KH, Tieu KV, Wang YG, et al. Maraviroc inhibits SARS-CoV-2 multiplication and s-protein mediated cell fusion in cell culture. BioRxiv [Preprint]. 2020. doi: 10.1101/2020.08.12.246389

 

  1. Okamoto M, Toyama M, Baba M. The chemokine receptor antagonist cenicriviroc inhibits the replication of SARS-CoV-2 in vitro. Antiviral Res. 2020;182:104902. doi: 10.1016/J.ANTIVIRAL.2020.104902

 

  1. García-Lledó A, Gómez-Pavón J, del Castillo JG, et al. Pharmacological treatment of COVID-19: An opinion paper. Rev Esp Quimioter. 2021;35(2):115-130. doi: 10.37201/req/158.2021

 

  1. Vellingiri B, Jayaramayya K, Iyer M, et al. COVID-19: A promising cure for the global panic. Sci Total Environ. 2020;725:138277. doi: 10.1016/j.scitotenv.2020.138277

 

  1. Gidari A, Sabbatini S, Pallotto C, et al. Nelfinavir: An old ally in the COVID-19 fight? Microorganisms. 2022;10(12):2471. doi: 10.3390/microorganisms10122471

 

  1. Uraki R, Ito M, Kiso M, et al. Efficacy of antivirals and bivalent mRNA vaccines against SARS-CoV-2 isolate CH1.1. Lancet Infect Dis. 2023;23:522-526. doi: 10.1016/S1473-3099(23)00132-9

 

  1. Rezkikov LR, Norris MH, Vashisht R, et al. Identification of antiviral antihistamines for COVID-19 repurposing. Biochem Biophys Res Commun. 2021;29:173-179. doi: 10.1016/j.bbrc.2020.11.095

 

  1. Basha SH. Coronavirus drugs-a brief overview of past, present and future. J PeerSci. 2020;2(2):e1000013.

 

  1. Meini S, Pagotto A, Longo B, Vendramin I, Pecori D, Tascini C. Role of Lopinavir/Ritonavir in the treatment of Covid-19: A review of current evidence, guideline recommendations, and perspectives. J Clin Med. 2020;9(7):2050. doi: 10.3390/jcm9072050

 

  1. Burastero GJ, Orlando G, Santoro A, et al. Ceftazidime/ Avibactam in ventilator-associated pneumonia due to difficult-to-treat non-fermenter gram-negative bacteria in Covid-19 patients: A case series and review of the literature. Antibiotics (Basel). 2022;11(8):1007. doi: 10.3390/antibiotics11081007

 

  1. Nourian A, Khalili H, Ahmadinejad Z, et al. Efficacy and safety of sofosbuvir/ledipasvir in treatment of patients with COVID-19; A randomized clinical trial. Acta Biomed. 2021;91(4):e2020102. doi: 10.23750/abm.v91i4.10877

 

  1. Czarnogorski M, Benn P, McCoig C, et al. Brief report: Impact of COVID-19 on Cabotegravir plus Rilpivirine long-acting dosing across 6 ongoing global phase IIb and III clinical trials. J Acquir Immune Defic Syndr. 2022;91(2):157-161. doi: 10.1097/QAI.0000000000003031

 

  1. Parienti JJ, Prazuck T, Peyro-Saint-Paul L, et al. Effect of tenofovir disoproxil fumarate and emtricitabine on nasopharyngeal SARS-CoV-2 viral load burden amongst outpatients with COVID-19: A pilot, randomized, open-label phase 2 trial. EClinicalMedicine. 2021;38:100993. doi: 10.1016/j.eclinm.2021.100993

 

  1. Montejano R, de la Calle-Prieto F, Velasco M, et al. Tenofovir disoproxil fumarate/emtricitabine and baricitinib for patients at high risk of severe coronavirus disease 2019: The PANCOVID randomized clinical trial. Clin Infect Dis. 2022;76(3):e116-e125. doi: 10.1093/cid/ciac628

 

  1. Rossignol JF, Bardin MC, Fulgencio J, Mogelnicki D, Bréchot C. A randomized double-blind placebo-controlled clinical trial of nitazoxanide for treatment of mild or moderate COVID-19. EClinicalMedicine. 2022;45:101310. doi: 10.1016/j.eclinm.2022.101310

 

  1. Zhai MZ, Lye CT, Kesselheim AS. Need for transparency and reliable evidence in emergency use authorizations for coronavirus disease 2019 (COVID-19) therapies. JAMA Intern Med. 2020;180(9):1145-1146. doi: 10.1001/jamainternmed.2020.2402

 

  1. Geetanjali S, Srivastava R, Singh R. Synthesis of four heterocyclic drug molecules repurposed for COVID-19. Mini Rev Org Chem. 2022;19(2):180-187. doi: 10.2174/1570193X18666210325121225

 

  1. Joshi S, Parkar J, Ansari A, et al. Role of favipiravir in the treatment of COVID-19. Int J Infect Dis. 2021;102:501-508. doi: 10.1016/j.ijid.2020.10.069

 

  1. Rabie AM. Efficacious preclinical repurposing of the nucleoside analogue didanosine against COVID-19 polymerase and exonuclease. ACS Omega. 2022;7:21385-21396. doi: 10.1021/acsomega.1c07095

 

  1. Cento V, Perno CF. Dolutegravir plus lamivudine two-drug regimen: Safety, efficacy and diagnostic considerations for its use in real-life clinical practice-a refined approach in the COVID-19 era. Diagnostics (Basel). 2021;11(5):809. doi: 10.3390/diagnostics11050809

 

  1. Heidary F, Madani S, Gharebaghi R, Asadi-Amoli F. Acyclovir as a potential add-on therapy in COVID-19 treatment regimes. Pharm Sci. 2021;27(Suppl 1):S68-S77. doi: 10.34172/PS.2021.38

 

  1. Meng M, Zhang S, Dong X, et al. COVID-19 associated EBV reactivation and effects of ganciclovir treatment. Immun Inflamm Dis. 2022;10(4):e597. doi: 10.1002/iid3.597
Conflict of interest
The authors declare no conflicts of interest.
Share
Back to top
INNOSC Theranostics and Pharmacological Sciences, Electronic ISSN: 2705-0823 Published by AccScience Publishing