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Coronaviruses

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ISSN (Print): 2666-7967
ISSN (Online): 2666-7975

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Research Article

Homology Modeling of Coronavirus Structural Proteins and Molecular Docking of Potential Drug Candidates for the Treatment of COVID-19

Author(s): Ahmed Adebayo Ishola* and Nnaemeka Tobechukwu Asogwa

Volume 2, Issue 2, 2021

Published on: 01 August, 2020

Page: [241 - 250] Pages: 10

DOI: 10.2174/2666796701999200802040704

Abstract

Background: The discovery of a novel strain of coronavirus in 2019 (COVID-19) has triggered a series of tragic events in the world with thousands of deaths recorded daily. Despite the huge resources committed to the discovery of vaccines against this highly pathogenic virus, scientists are still unable to find suitable treatments for the disease. Understanding the structure of coronavirus proteins could provide a basis for the development of cheap, potent and, less toxic vaccines.

Objective: This study was therefore designed to model coronavirus spike (S) glycoprotein and envelope (E) protein as well as to carry out molecular docking of potential drugs to the homologs and coronavirus main protease (Mpro).

Methods: Homology modeling of coronavirus spike (S) glycoprotein and envelope (E) protein was carried out using sequence deposited in the Uniprot database. The topological features of the model’s catalytic site were evaluated using the CASTp server. Compounds reported as potential drugs against COVID-19 were docked to S glycoprotein, E protein, and coronavirus main protease (Mpro) to determine the best ligands and the mode of interaction.

Results: Homology modeling of the proteins revealed structures with 91-98% sequence similarity with PDB entries. The catalytic site of the modeled proteins contained conserved residue involved in ligand binding. In addition, remdesivir, lopinavir, and ritonavir have a high binding affinity for the three proteins studied interacting with key residues in the protein’s catalytic domain.

Conclusion: Results from the study revealed that remdesivir, lopinavir, and ritonavir are inhibitors of key coronavirus proteins and therefore qualify for further studies as a potential treatment for coronavirus.

Keywords: Coronavirus, homology modeling, spike glycoprotein, envelope protein, main protease, molecular docking.

[1]
World Health Organization, Coronavirus diseaseAvailable from: https://www.who.int/emergencies/diseases/novel-coronavirus-2019/situation-reports
[2]
Chan JFW, Lau SKP, To KKW, Cheng VCC, Woo PCY, Yuen KY. Middle East respiratory syndrome coronavirus: another zoonotic betacoronavirus causing SARS-like disease. Clin Microbiol Rev 2015; 28(2): 465-522.
[http://dx.doi.org/10.1128/CMR.00102-14] [PMID: 25810418]
[3]
Lau SKP, Woo PCY, Li KSM, et al. Discovery of a novel coronavirus, China Rattus coronavirus HKU24, from Norway rats supports the murine origin of Betacoronavirus 1 and has implications for the ancestor of Betacoronavirus lineage A. J Virol 2015; 89(6): 3076-92.
[http://dx.doi.org/10.1128/JVI.02420-14] [PMID: 25552712]
[4]
Elfiky AA, Mahdy SM, Elshemey WM. Quantitative structure-activity relationship and molecular docking revealed a potency of anti-hepatitis C virus drugs against human corona viruses. J Med Virol 2017; 89(6): 1040-7.
[http://dx.doi.org/10.1002/jmv.24736] [PMID: 27864902]
[5]
Luo C-M, Wang N, Yang X-L, et al. Discovery of novel bat Coronaviruses in South China that use the same receptor as Middle East respiratory syndrome Coronavirus. J Virol 2018; 92(13): e00116-8.
[http://dx.doi.org/10.1128/JVI.00116-18] [PMID: 29669833]
[6]
Schoeman D, Fielding BC. Coronavirus envelope protein: current knowledge. Virol J 2019; 16(1): 69.
[http://dx.doi.org/10.1186/s12985-019-1182-0] [PMID: 31133031]
[7]
Gallagher TM, Buchmeier MJ. Coronavirus spike proteins in viral entry and pathogenesis. Virology 2001; 279(2): 371-4.
[http://dx.doi.org/10.1006/viro.2000.0757] [PMID: 11162792]
[8]
Hofmann H, Pöhlmann S. Cellular entry of the SARS coronavirus. Trends Microbiol 2004; 12(10): 466-72.
[http://dx.doi.org/10.1016/j.tim.2004.08.008] [PMID: 15381196]
[9]
Dimitrov DS. The secret life of ACE2 as a receptor for the SARS virus. Cell 2003; 115(6): 652-3.
[http://dx.doi.org/10.1016/S0092-8674(03)00976-0] [PMID: 14675530]
[10]
Li W, Moore MJ, Vasilieva N, et al. Angiotensin-converting enzyme 2 is a functional receptor for the SARS coronavirus. Nature 2003; 426(6965): 450-4.
[http://dx.doi.org/10.1038/nature02145] [PMID: 14647384]
[11]
He Y, Li J, Li W, Lustigman S, Farzan M, Jiang S. Cross-neutralization of human and palm civet severe acute respiratory syndrome coronaviruses by antibodies targeting the receptor-binding domain of spike protein. J Immunol 2006; 176(10): 6085-92.
[http://dx.doi.org/10.4049/jimmunol.176.10.6085] [PMID: 16670317]
[12]
Li F. Structure, function, and evolution of Coronavirus spike proteins. Annu Rev Virol 2016; 3(1): 237-61.
[http://dx.doi.org/10.1146/annurev-virology-110615-042301] [PMID: 27578435]
[13]
Raamsman MJB, Locker JK, de Hooge A, et al. Characterization of the coronavirus mouse hepatitis virus strain A59 small membrane protein E. J Virol 2000; 74(5): 2333-42.
[http://dx.doi.org/10.1128/JVI.74.5.2333-2342.2000] [PMID: 10666264]
[14]
Curtis KM, Yount B, Baric RS. Heterologous gene expression from transmissible gastroenteritis virus replicon particles J Virol 2002 2002; 76(3): 1422-34
[15]
Anand K, Ziebuhr J, Wadhwani P, Mesters JR, Hilgenfeld R. Coronavirus main proteinase (3CLpro) structure: basis for design of anti-SARS drugs. Science 2003; 300(5626): 1763-7.
[http://dx.doi.org/10.1126/science.1085658] [PMID: 12746549]
[16]
Hilgenfeld R. From SARS to MERS: crystallographic studies on coronaviral proteases enable antiviral drug design. FEBS J 2014; 281(18): 4085-96.
[http://dx.doi.org/10.1111/febs.12936] [PMID: 25039866]
[17]
Hegyi A, Ziebuhr J. Conservation of substrate specificities among coronavirus main proteases. J Gen Virol 2002; 83(Pt 3): 595-9.
[http://dx.doi.org/10.1099/0022-1317-83-3-595] [PMID: 11842254]
[18]
de Haan CAM, Vennema H, Rottier PJM. Assembly of the coronavirus envelope: homotypic interactions between the M proteins. J Virol 2000; 74(11): 4967-78.
[http://dx.doi.org/10.1128/JVI.74.11.4967-4978.2000] [PMID: 10799570]
[19]
Krieger E, Nabuurs SB, Vriend G. Homology modeling. Methods Biochem Anal 2003; 44: 509-23.
[PMID: 12647402]
[20]
Bordoli L, Kiefer F, Arnold K, Benkert P, Battey J, Schwede T. Protein structure homology modeling using SWISS-MODEL workspace. Nat Protoc 2009; 4(1): 1-13.
[http://dx.doi.org/10.1038/nprot.2008.197]
[21]
Biasini M, Bienert S, Waterhouse A, et al. SWISS-MODEL: modelling protein tertiary and quaternary structure using evolutionary information. Nucleic Acids Res 2014; 42W252-8
[http://dx.doi.org/10.1093/nar/gku340] [PMID: 24782522]
[22]
Benkert P, Tosatto SCE, Schomburg D. QMEAN: a comprehensive scoring function for model quality assessment. Proteins 2008; 71(1): 261-77.
[http://dx.doi.org/10.1002/prot.21715] [PMID: 17932912]
[23]
Benkert P, Künzli M, Schwede T. QMEAN server for protein model quality estimationNucleic Acids Res 2009; 37(suppl_2): W510-4
[http://dx.doi.org/10.1093/nar/gkp322]
[24]
Laskowski RA, MacArthur MW, Moss DS, Thornton JM. PROCHECK: a program to check the stereochemical quality of protein structures. J Appl Cryst 1993; 26(2): 283-91.
[http://dx.doi.org/10.1107/S0021889892009944]
[25]
Van Gunsteren W, Billeter S, Eising A, et al. Biomolecular simulations: the GROMOS96 manual and user guide. Zurich, Groningen 1996.
[26]
Tian W, Chen C, Lei X, Zhao J, Liang J. CASTp 3.0: computed atlas of surface topography of proteins. Nucleic Acids Res 2018; 46(W1)W363-7
[http://dx.doi.org/10.1093/nar/gky473] [PMID: 29860391]
[27]
O’Boyle NM, Banck M, James CA, Morley C, Vandermeersch T, Hutchison GR. Open Babel: an open chemical toolbox. J Cheminform 2011; 3: 33.
[http://dx.doi.org/10.1186/1758-2946-3-33] [PMID: 21982300]
[28]
Trott O, Olson AJ. AutoDock Vina: improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading. J Comput Chem 2010; 31(2): 455-61.
[PMID: 19499576]
[29]
Cavasotto CN, Phatak SS. Homology modeling in drug discovery: current trends and applications. Drug Discov Today 2009; 14(13-14): 676-83.
[http://dx.doi.org/10.1016/j.drudis.2009.04.006] [PMID: 19422931]
[30]
Wong SK, Li W, Moore MJ, Choe H, Farzan M. A 193-amino acid fragment of the SARS coronavirus S protein efficiently binds angiotensin-converting enzyme 2. J Biol Chem 2004; 279(5): 3197-201.
[http://dx.doi.org/10.1074/jbc.C300520200] [PMID: 14670965]
[31]
Kuo L, Hurst KR, Masters PS. Exceptional flexibility in the sequence requirements for coronavirus small envelope protein function. J Virol 2007; 81(5): 2249-62.
[http://dx.doi.org/10.1128/JVI.01577-06] [PMID: 17182690]
[32]
Tok TT, Tatar G. Structures and functions of coronavirus proteins: molecular modeling of viral nucleoprotein. Int J Virol Infect Dis 2017; 2(1): 1-7.
[33]
Parthasarathy K, Ng L, Lin X, et al. Structural flexibility of the pentameric SARS coronavirus envelope protein ion channel. Biophys J 2008; 95(6): L39-41.
[http://dx.doi.org/10.1529/biophysj.108.133041] [PMID: 18658207]
[34]
Ziebuhr J, Snijder EJ, Gorbalenya AE. Virus-encoded proteinases and proteolytic processing in the Nidovirales. J Gen Virol 2000; 81(Pt 4): 853-79.
[http://dx.doi.org/10.1099/0022-1317-81-4-853] [PMID: 10725411]
[35]
Peele KA, Chandrasai P, Srihansa T, et al. Molecular docking and dynamic simulations for antiviral compounds against SARS-CoV-2: a computational study. Informatics Med Unlocked 2020; 19100345
[http://dx.doi.org/10.1016/j.imu.2020.100345]]
[36]
Hull MW, Montaner JSG. Ritonavir-boosted protease inhibitors in HIV therapy. Ann Med 2011; 43(5): 375-88.
[http://dx.doi.org/10.3109/07853890.2011.572905] [PMID: 21501034]
[37]
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 2020.35101646
[http://dx.doi.org/10.1016/j.tmaid.2020.101646] [PMID: 32294562]
[38]
Mulangu S, Dodd LE, Davey RT Jr, et al. A randomized, controlled trial of Ebola virus disease therapeutics. N Engl J Med 2019; 381(24): 2293-303.
[http://dx.doi.org/10.1056/NEJMoa1910993] [PMID: 31774950]
[39]
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): 269-71.
[http://dx.doi.org/10.1038/s41422-020-0282-0] [PMID: 32020029]
[40]
Cao B, Wang Y, Wen D, et al. A trial of lopinavir-ritonavir in adults hospitalized with severe COVID-19. N Engl J Med 2020; 382(19): 1787-99.
[http://dx.doi.org/10.1056/NEJMoa2001282] [PMID: 32187464]
[41]
Chu CM, Cheng VCC, Hung IFN, et al. Role of lopinavir/ritonavir in the treatment of SARS: initial virological and clinical findings. Thorax 2004; 59(3): 252-6.
[http://dx.doi.org/10.1136/thorax.2003.012658] [PMID: 14985565]

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