Login Register Cart 0
Generic placeholder image

Current Pharmaceutical Biotechnology

Editor-in-Chief

ISSN (Print): 1389-2010
ISSN (Online): 1873-4316

Back
Journal Home About Journal Editorial Board Journal Insight Current Issue Volumes/Issues
Subscribe
Research Article

Identification of Novel Drug Candidates for the Inhibition of Catalytic Cleavage Activity of Coronavirus 3CL-like Protease Enzyme

Author(s): Arun Bahadur Gurung*, Khalid Mashay Al-Anazi, Mohammad Ajmal Ali, Joongku Lee and Mohammad Abul Farah*

Volume 23, Issue 7, 2022

Published on: 03 August, 2021

Page: [959 - 969] Pages: 11

DOI: 10.2174/1389201022666210604150041

Price: $65

Abstract

Background: There has been tremendous pressure on healthcare facilities globally due to the recent emergence of novel coronavirus infection known as COVID-19 and its rapid spread across the continents. The lack of effective therapeutics for the management of the pandemic calls for the discovery of new drugs and vaccines.

Objective: In the present study, a chemical library was screened for molecules against three coronavirus 3CL-like protease enzymes (SARS-CoV-2 3CLpro, SARS-CoV 3CLpro and MERS-CoV 3CLpro), which are a key player in the viral replication cycle.

Methods: Extensive computational methods such as virtual screening and molecular docking were employed in this study.

Results: Two lead molecules, ZINC08825480 (4-bromo-N'-{(E)-[1-phenyl-3-(pyridin-3-yl)-1H-pyrazol- 4-yl]methylidene}benzene-1-sulfonohydrazide) and ZINC72009942 (N-[[2-[[(3S)-3-methyl-1-piperidyl] methyl]phenyl]methyl]-6-oxo-1-(p-tolyl)-4,5-dihydro-1,2,4-triazine-3-carboxamide), were identified with better affinity with the three target enzymes as compared to the approved antiviral drugs. Both the lead molecules possessed favorable drug-like properties, fit well into the active site pocket close to His- Cys dyad and showed a good number of hydrogen bonds with the backbone as well as side chains of key amino acid residues.

Conclusion: Thus, the present study offers two novel chemical entities against coronavirus infections which can be validated through various biological assays.

Keywords: 3CL-like protease, main protease, SARS-CoV-2 3CLpro , SARS-CoV 3CLpro, MERS-CoV 3CLpro, antiviral drugs.

« Previous Next »
Graphical Abstract

[1]
Holmes, K.V.; Lai, M.M.C. Coronaviridae: The viruses and their replication. Fields Virol., 1996, 3, 1075-1093.
[2]
Bedford, J.; Enria, D.; Giesecke, J.; Heymann, D.L.; Ihekweazu, C.; Kobinger, G.; Lane, H.C.; Memish, Z.; Oh, M.D.; Sall, A.A.; Schuchat, A.; Ungchusak, K.; Wieler, L.H. WHO strategic and technical advisory group for infectious hazards. COVID-19: towards controlling of a pandemic. Lancet, 2020, 395(10229), 1015-1018.
[http://dx.doi.org/10.1016/S0140-6736(20)30673-5] [PMID: 32197103]
[3]
Memish, Z.A.; Mishra, N.; Olival, K.J.; Fagbo, S.F.; Kapoor, V.; Epstein, J.H.; Alhakeem, R.; Durosinloun, A.; Al Asmari, M.; Islam, A.; Kapoor, A.; Briese, T.; Daszak, P.; Al Rabeeah, A.A.; Lipkin, W.I. Middle East respiratory syndrome coronavirus in bats, Saudi Arabia. Emerg. Infect. Dis., 2013, 19(11), 1819-1823.
[http://dx.doi.org/10.3201/eid1911.131172] [PMID: 24206838]
[4]
Peiris, J.S.M.; Yuen, K.Y.; Osterhaus, A.D.M.E.; Stöhr, K. The severe acute respiratory syndrome. N. Engl. J. Med., 2003, 349(25), 2431-2441.
[http://dx.doi.org/10.1056/NEJMra032498] [PMID: 14681510]
[5]
Zhou, J.; Fang, L.; Yang, Z.; Xu, S.; Lv, M.; Sun, Z.; Chen, J.; Wang, D.; Gao, J.; Xiao, S. Identification of novel proteolytically inactive mutations in coronavirus 3C-like protease using a combined approach. FASEB J., 2019, 33(12), 14575-14587.
[http://dx.doi.org/10.1096/fj.201901624RR] [PMID: 31690127]
[6]
Fung, T.S.; Liu, D.X. Human coronavirus: Host-pathogen interaction. Annu. Rev. Microbiol., 2019, 73, 529-557.
[http://dx.doi.org/10.1146/annurev-micro-020518-115759] [PMID: 31226023]
[7]
Masters, P.S. The molecular biology of coronaviruses. Adv. Virus Res., 2006, 66, 193-292.
[http://dx.doi.org/10.1016/S0065-3527(06)66005-3] [PMID: 16877062]
[8]
Liu, D.X.; Inglis, S.C. Association of the infectious bronchitis virus 3c protein with the virion envelope. Virol., 1991, 185(2), 911-917.
[http://dx.doi.org/10.1016/0042-6822(91)90572-S] [PMID: 1962461]
[9]
de Souza Luna, L.K.; Heiser, V.; Regamey, N.; Panning, M.; Drexler, J.F.; Mulangu, S.; Poon, L.; Baumgarte, S.; Haijema, B.J.; Kaiser, L.; Drosten, C. Generic detection of coronaviruses and differentiation at the prototype strain level by reverse transcription-PCR and nonfluorescent low-density microarray. J. Clin. Microbiol., 2007, 45(3), 1049-1052.
[http://dx.doi.org/10.1128/JCM.02426-06] [PMID: 17229859]
[10]
Lai, M.M.C.; Cavanagh, D. The molecular biology of coronaviruses. Adv. Virus Res; Elsevier, 1997, pp. 1-100.
[11]
Siddell, S.G. The coronaviridae: An introduction.In The Coronaviridae; Springer, 1995, pp. 1-10.
[http://dx.doi.org/10.1007/978-1-4899-1531-3_1]
[12]
de Haan, C.A.M.; van Genne, L.; Stoop, J.N.; Volders, H.; Rottier, P.J.M. Coronaviruses as vectors: Position dependence of foreign gene expression. J. Virol., 2003, 77(21), 11312-11323.
[http://dx.doi.org/10.1128/JVI.77.21.11312-11323.2003] [PMID: 14557617]
[13]
Perlman, S.; Netland, J. Coronaviruses post-SARS: Update on replication and pathogenesis. Nat. Rev. Microbiol., 2009, 7(6), 439-450.
[http://dx.doi.org/10.1038/nrmicro2147] [PMID: 19430490]
[14]
Zhu, X.; Wang, D.; Zhou, J.; Pan, T.; Chen, J.; Yang, Y.; Lv, M.; Ye, X.; Peng, G.; Fang, L.; Xiao, S. Porcine delta coronavirus nsp5 antagonizes type I interferon signaling by cleaving STAT2. J. Virol., 2017, 91(10), e00003-e00017.
[http://dx.doi.org/10.1128/JVI.00003-17] [PMID: 28250121]
[15]
Yang, H.; Xie, W.; Xue, X.; Yang, K.; Ma, J.; Liang, W.; Zhao, Q.; Zhou, Z.; Pei, D.; Ziebuhr, J.; Hilgenfeld, R.; Yuen, K.Y.; Wong, L.; Gao, G.; Chen, S.; Chen, Z.; Ma, D.; Bartlam, M.; Rao, Z. Design of wide-spectrum inhibitors targeting coronavirus main proteases. PLoS Biol., 2005, 3(10)e324
[http://dx.doi.org/10.1371/journal.pbio.0030324] [PMID: 16128623]
[16]
Bacha, U.; Barrila, J.; Velazquez-Campoy, A.; Leavitt, S.A.; Freire, E. Identification of novel inhibitors of the SARS coronavirus main protease 3CLpro. Biochemistry, 2004, 43(17), 4906-4912.
[http://dx.doi.org/10.1021/bi0361766] [PMID: 15109248]
[17]
Blanchard, J.E.; Elowe, N.H.; Huitema, C.; Fortin, P.D.; Cechetto, J.D.; Eltis, L.D.; Brown, E.D. High-throughput screening identifies inhibitors of the SARS coronavirus main proteinase. Chem. Biol., 2004, 11(10), 1445-1453.
[http://dx.doi.org/10.1016/j.chembiol.2004.08.011] [PMID: 15489171]
[18]
Chen, C-N.; Lin, C.P.C.; Huang, K-K.; Chen, W-C.; Hsieh, H-P.; Liang, P-H.; Hsu, J.T-A. Inhibition of SARS-CoV 3C-like protease activity by theaflavin-3, 3′-digallate (TF3). Evid. Based Complement. Alternat. Med., 2005, 2(2), 209-215.
[http://dx.doi.org/10.1093/ecam/neh081] [PMID: 15937562]
[19]
Chen, L.; Chen, S.; Gui, C.; Shen, J.; Shen, X.; Jiang, H. Discovering severe acute respiratory syndrome coronavirus 3CL protease inhibitors: virtual screening, surface plasmon resonance, and fluorescence resonance energy transfer assays. J. Biomol. Screen., 2006, 11(8), 915-921.
[http://dx.doi.org/10.1177/1087057106293295] [PMID: 17092912]
[20]
Jo, S.; Kim, H.; Kim, S.; Shin, D.H.; Kim, M-S. Characteristics of flavonoids as potent MERS-CoV 3C-like protease inhibitors. Chem. Biol. Drug Des., 2019, 94(6), 2023-2030.
[http://dx.doi.org/10.1111/cbdd.13604] [PMID: 31436895]
[21]
Jo, S.; Kim, S.; Shin, D.H.; Kim, M-S. Inhibition of SARS-CoV 3CL protease by flavonoids. J. Enzyme Inhib. Med. Chem., 2020, 35(1), 145-151.
[http://dx.doi.org/10.1080/14756366.2019.1690480] [PMID: 31724441]
[22]
Sisay, M. 3CLpro inhibitors as a potential therapeutic option for COVID-19: Available evidence and ongoing clinical trials. Pharmacol. Res., 2020, 156104779
[http://dx.doi.org/10.1016/j.phrs.2020.104779] [PMID: 32247821]
[23]
Sterling, T.; Irwin, J.J. ZINC 15--ligand discovery for everyone. J. Chem. Inf. Model., 2015, 55(11), 2324-2337.
[http://dx.doi.org/10.1021/acs.jcim.5b00559] [PMID: 26479676]
[24]
Kim, S.; Thiessen, P.A.; Bolton, E.E.; Chen, J.; Fu, G.; Gindulyte, A.; Han, L.; He, J.; He, S.; Shoemaker, B.A.; Wang, J.; Yu, B.; Zhang, J.; Bryant, S.H. PubChem substance and compound databases. Nucleic Acids Res., 2016, 44(D1), D1202-D1213.
[http://dx.doi.org/10.1093/nar/gkv951] [PMID: 26400175]
[25]
Lipinski, C.A. Lead- and drug-like compounds: the rule-of-five revolution. Drug Discov. Today. Technol., 2004, 1(4), 337-341.
[http://dx.doi.org/10.1016/j.ddtec.2004.11.007] [PMID: 24981612]
[26]
Veber, D.F.; Johnson, S.R.; Cheng, H-Y.; Smith, B.R.; Ward, K.W.; Kopple, K.D. Molecular properties that influence the oral bioavailability of drug candidates. J. Med. Chem., 2002, 45(12), 2615-2623.
[http://dx.doi.org/10.1021/jm020017n] [PMID: 12036371]
[27]
Sander, T.; Freyss, J.; von Korff, M.; Rufener, C. DataWarrior: an open-source program for chemistry aware data visualization and analysis. J. Chem. Inf. Model., 2015, 55(2), 460-473.
[http://dx.doi.org/10.1021/ci500588j] [PMID: 25558886]
[28]
Thompson, M.A. Molecular docking using ArgusLab, an efficient shape-based search algorithm and the AScore scoring function ACS Meeting, Philadelphia, 2004, p. 42.
[29]
Morris, G.M.; Huey, R.; Lindstrom, W.; Sanner, M.F.; Belew, R.K.; Goodsell, D.S.; Olson, A.J. AutoDock4 and AutoDockTools4: Automated docking with selective receptor flexibility. J. Comput. Chem., 2009, 30(16), 2785-2791.
[http://dx.doi.org/10.1002/jcc.21256] [PMID: 19399780]
[30]
Gurung, A.B.; Bhattacharjee, A.; Ali, M.A. Exploring the physicochemical profile and the binding patterns of selected novel anticancer Himalayan plant derived active compounds with macromolecular targets. Informatics Med. Unlocked, 2016, 5, 1-14.
[http://dx.doi.org/10.1016/j.imu.2016.09.004]

Rights & Permissions Print Cite
Article Metrics
19
1
© 2025 Bentham Science Publishers | Privacy Policy