Generic placeholder image

Coronaviruses

Editor-in-Chief

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

Research Article

Structure Based Drug Design Approach to Identify Potential SARS-CoV-2 Polymerase Inhibitors

Author(s): Preeya Negi, Surya Prakash and Vaishali M. Patil*

Volume 2, Issue 4, 2021

Published on: 12 November, 2020

Page: [507 - 515] Pages: 9

DOI: 10.2174/2666796701999201113114545

Abstract

Aims: The research work aims to apply the current virtual screening approaches for rapid screening of available compounds as inhibitors of the novel coronavirus (COVID-19).

Background: The worldwide pandemic, uncontrolled spread, and lack of effective therapeutics demand novel SARS-CoV-2 inhibitory anti-viral agents.

Objective: The major objectives of the present work are – i) effective utilization of open-source computer- aided drug design (CADD) tools; ii) to prepare a database according to chemical structure similarity to the reported anti-viral drug, Favipiravir; and iii) to investigate potential inhibitors of the novel coronavirus.

Methods: The dataset was prepared based on the chemical structure similarity feature of ChemSpider. The virtual screening was carried out using molecular docking and ADMET properties. For performing molecular docking studies, the standard docking protocol of iGEMDOCK was used.

Results: Based on chemical structure similarity search to Favipiravir, a small library of 40 compounds was designed. The docking score and ADMET properties were analyzed to prioritize the compounds.

Conclusion: The virtual screening resulted in the identification of potential anti-viral compounds. Among the designed library of compounds based on structural similarity to Favipiravir, 70% of compounds were found to possess docking scores more than that of Favipiravir. The amino acid residues involved in binding at the RNA dependent RNA polymerase (RdRp) were identified. The compounds have shown acceptable ADME properties and are potentially non-toxic.

Other: The study has successfully applied the open-source CADD tools to investigate the novel SARSCoV- 2 polymerase inhibitors.

Keywords: SARS-CoV-2, polymerase inhibitors, virtual screening, favipiravir, molecular docking, ADME properties.

Graphical Abstract
[1]
Yan X, Liao C, Liu Z, Hagler AT, Gu Q, Xu J. Chemical structure similarity search for ligand-based virtual screening: methods and computational resources. Curr Drug Targets 2015; 16(999)
[PMID: 26521773]
[2]
Furuta Y, Takahashi K, Fukuda Y, et al. In vitro and in vivo activities of anti-influenza virus compound T-705. Antimicrob Agents Chemother 2002; 46(4): 977-81.
[http://dx.doi.org/10.1128/AAC.46.4.977-981.2002] [PMID: 11897578]
[3]
Antonov L. Favipiravir tautomerism: A short theoretical report. ChemRxiv 2020.
[http://dx.doi.org/10.26434/chemrxiv.12115620.v1]
[4]
Gowen BB, Wong MH, Jung KH, et al. In vitro and in vivo activities of T-705 against arenavirus and bunyavirus infections. Antimicrob Agents Chemother 2007; 51(9): 3168-76.
[http://dx.doi.org/10.1128/AAC.00356-07] [PMID: 17606691]
[5]
Safronetz D, Falzarano D, Scott DP, Furuta Y, Feldmann H, Gowen BB. Anti-viral efficacy of favipiravir against two prominent etiological agents of hantavirus pulmonary syndrome. Antimicrob Agents Chemother 2013; 57(10): 4673-80.
[http://dx.doi.org/10.1128/AAC.00886-13] [PMID: 23856782]
[6]
Morrey JD, Taro BS, Siddharthan V, et al. Efficacy of orally administered T-705 pyrazine analog on lethal West Nile virus infection in rodents. Antiviral Res 2008; 80(3): 377-9.
[http://dx.doi.org/10.1016/j.antiviral.2008.07.009] [PMID: 18762216]
[7]
Rocha-Pereira J, Jochmans D, Dallmeier K, Leyssen P, Nascimento MS, Neyts J. Favipiravir (T-705) inhibits in vitro norovirus replication. Biochem Biophys Res Commun 2012; 424(4): 777-80.
[http://dx.doi.org/10.1016/j.bbrc.2012.07.034] [PMID: 22809499]
[8]
Oestereich L, Lüdtke A, Wurr S, Rieger T, Muñoz-Fontela C, Günther S. Successful treatment of advanced Ebola virus infection with T-705 (favipiravir) in a small animal model. Antiviral Res 2014; 105: 17-21.
[http://dx.doi.org/10.1016/j.antiviral.2014.02.014] [PMID: 24583123]
[9]
Mentré F, Taburet AM, Guedj J, et al. Dose regimen of favipiravir for Ebola virus disease. Lancet Infect Dis 2015; 15(2): 150-1.
[http://dx.doi.org/10.1016/S1473-3099(14)71047-3] [PMID: 25435054]
[10]
Scharton D, Bailey KW, Vest Z, et al. Favipiravir (T-705) protects against peracute Rift Valley fever virus infection and reduces delayed-onset neurologic disease observed with ribavirin treatment. Antiviral Res 2014; 104: 84-92.
[http://dx.doi.org/10.1016/j.antiviral.2014.01.016] [PMID: 24486952]
[11]
Smee DF, Hurst BL, Wong MH, et al. Effects of the combination of favipiravir (T-705) and oseltamivir on influenza A virus infections in mice. Antimicrob Agents Chemother 2010; 54(1): 126-33.
[http://dx.doi.org/10.1128/AAC.00933-09] [PMID: 19901093]
[12]
Rosenke K, Feldmann H, Westover JB, et al. Use of Favipiravir to treat lassa virus infection in Macaques. Emerg Infect Dis 2018; 24(9): 1696-9.
[http://dx.doi.org/10.3201/eid2409.180233] [PMID: 29882740]
[13]
Raabe VN, Kann G, Ribner BS, et al. Emory serious communicable diseases unit. Favipiravir and ribavirin treatment of epidemiologically linked cases of lassa fever. Clin Infect Dis 2017; 65(5): 855-9.
[http://dx.doi.org/10.1093/cid/cix406] [PMID: 29017278]
[14]
Delang L, Abdelnabi R, Neyts J. Favipiravir as a potential countermeasure against neglected and emerging RNA viruses. Antiviral Res 2018; 153: 85-94.
[http://dx.doi.org/10.1016/j.antiviral.2018.03.003] [PMID: 29524445]
[15]
Shiraki K, Daikoku T. Favipiravir, an anti-influenza drug against life-threatening RNA virus infections. Pharmacol Ther 2020.209107512
[http://dx.doi.org/10.1016/j.pharmthera.2020.107512] [PMID: 32097670]
[16]
Fortune. www.fortune.com (accessed on 15th August 2020)
[17]
Chemspider. www.chemspider.com (accessed on 15th August 2020)
[18]
A structural view of biology. http://www.rcsb.org (accessed on 15th August 2020)
[19]
Kirchdoerfer RN, Ward AB. Structure of the SARS-CoV nsp12 polymerase bound to nsp7 and nsp8 cofactors. Nat Comm 2019; 10: 2342.
[20]
Gao Y, Yan L, Huang Y, et al. Structure of the RNA-dependent RNA polymerase from COVID-19 virus. Science 2020; 368(6492): 779-82.
[http://dx.doi.org/10.1126/science.abb7498] [PMID: 32277040]
[21]
Jin Z, Du X, Xu Y, et al. Structure of Mpro from SARS-CoV-2 and discovery of its inhibitors. Nature 2020; 582(7811): 289-93.
[http://dx.doi.org/10.1038/s41586-020-2223-y] [PMID: 32272481]
[22]
Hsu KC, Chen YF, Lin SR, Yang JM. iGEMDOCK: a graphical environment of enhancing GEMDOCK using pharmacological interactions and post-screening analysis. BMC Bioinformatics 2011; 12(Suppl. 1): S33.
[http://dx.doi.org/10.1186/1471-2105-12-S1-S33] [PMID: 21342564]
[23]
Liu C, Zhou Q, Li Y, et al. Research and development on therapeutic agents and vaccines for COVID-19 and related human coronavirus diseases. ACS Cent Sci 2020; 6(3): 315-31.
[http://dx.doi.org/10.1021/acscentsci.0c00272] [PMID: 32226821]
[24]
Chang Y, Tung Y, Lee K, et al. Potential therapeutic agents for COVID-19 based on the analysis of protease and RNA Polymerase Docking. Preprints 2020; 2020020242
[http://dx.doi.org/10.20944/preprints202002.0242.v1]
[25]
Dong L, Hu S, Gao J. Discovering drugs to treat coronavirus disease 2019 (COVID-19). Drug Discov Ther 2020; 14(1): 58-60.
[http://dx.doi.org/10.5582/ddt.2020.01012] [PMID: 32147628]
[26]
Cooinspeaker. China approves favipiravir as potent treatment against new coronavirus COVID-19 strain. Available from: www.coinspeaker.com/china-favipiravir-cornoavirus-covid-19
[27]
Day A, Williams A, Batchelor C, Kidd R, Tkachenko V. Practical solutions to common challenges in the pharmaceutical industry and beyond.In: Harland Lee, Forster M, Eds. Open source software in life science research. Woodhead Publishing Series in Biomedicine In: 2012; pp. 63-87.
[http://dx.doi.org/10.1533/9781908818249.63]

© 2022 Bentham Science Publishers | Privacy Policy