Login Register Cart 0
Generic placeholder image

Letters in Drug Design & Discovery

Editor-in-Chief

ISSN (Print): 1570-1808
ISSN (Online): 1875-628X

Back
Research Article

Discovery of Potential Compounds Against SARS-CoV-2 Based on 3CLpro/RdRp Dual-target: An In silico Approach

Author(s): Jiaojiao Li, Lin Zhu, Zheng Qin, Zhengfu Li, Xun Gao, Jing Ji* and Jinyang Shen*

Volume 20, Issue 11, 2023

Published on: 16 September, 2022

Page: [1846 - 1860] Pages: 15

DOI: 10.2174/1570180819666220818145647

Price: $65

Abstract

Background: The COVID-19 outbreak is a serious concern and has caused a great loss to the global economy. Therefore, COVID-19 has become an urgent public health problem. Although new vaccines and small molecule drugs are now available, these prevention and treatment methods cannot completely control the epidemic due to the constant mutation of SARS-CoV-2. Targeting 3CLpro/RdRp is expected to develop drugs that are not susceptible to the mutation of SARS-COV-2, and it will also have a certain effect on the coronavirus that may appear in the future.

Objective: This study aimed to find small molecules against SARS-CoV-2 with research potential and provide relevant data for the rational development of anti-SARS-COV-2 drugs.

Methods: Targeting 3CLpro/RdRp, using Shards database (120,000 natural small molecule compounds) in the ZINC database, adopting a step-by-step screening strategy, and taking Lopinavir, Indinavir, and Molnupiravir as screening criteria was done. Moreover, the top scoring compounds were screened using rigid docking, and molecular dynamics simulation and ADME prediction were performed. Finally, the molecules with better scores were screened out.

Results: After molecular docking with 3CLpro as the target, 3207 compounds meeting the screening criteria were obtained. After applying Lipinski's rule of five for drug property screening, 1825 compounds that met the criteria were obtained. After molecular docking with RdRp as the target, ZINC04259665 has a good docking score. According to molecular dynamics simulation results, ZINC04259665 is stable in combination with 3CLpro/RdRp. ADME prediction shows that ZINC04259665 has good druggability.

Conclusion: Using 3CLpro/RdRp targets and then using a step-by-step strategy to screen the compound with the highest score through molecular dynamics simulation and ADME prediction, it was found that ZINC04259665 has good development potential and can be used as a follow-up hit compound for research. In addition, the data obtained provide relevant information for the rational development of anti- SARS-COV-2 drugs.

Keywords: SARS-COV-2, 3CLpro, RdRp, in silico studies, SWISS-bioinformatics, molecular dynamics.

« Previous Next »
Graphical Abstract

[1]
Guan, W.J.; Ni, Z.Y.; Hu, Y.; Liang, W.H.; Ou, C.Q.; He, J.X.; Liu, L.; Shan, H.; Lei, C.L.; Hui, D.S.C.; Du, B.; Li, L.J.; Zeng, G.; Yuen, K.Y.; Chen, R.C.; Tang, C.L.; Wang, T.; Chen, P.Y.; Xiang, J.; Li, S.Y.; Wang, J.L.; Liang, Z.J.; Peng, Y.X.; Wei, L.; Liu, Y.; Hu, Y.H.; Peng, P.; Wang, J.M.; Liu, J.Y.; Chen, Z.; Li, G.; Zheng, Z.J.; Qiu, S.Q.; Luo, J.; Ye, C.J.; Zhu, S.Y.; Zhong, N.S. Clinical characteristics of coronavirus disease 2019 in China. N. Engl. J. Med., 2020, 382(18), 1708-1720.
[http://dx.doi.org/10.1056/NEJMoa2002032] [PMID: 32109013]
[2]
Harapan, H.; Itoh, N.; Yufika, A.; Winardi, W.; Keam, S.; Te, H.; Megawati, D.; Hayati, Z.; Wagner, A.L.; Mudatsir, M. Coronavirus disease 2019 (COVID-19): A literature review. J. Infect. Public Health, 2020, 13(5), 667-673.
[http://dx.doi.org/10.1016/j.jiph.2020.03.019] [PMID: 32340833]
[3]
Wiersinga, W.J.; Rhodes, A.; Cheng, A.C.; Peacock, S.J.; Prescott, H.C. Pathophysiology, transmission, diagnosis, and treatment of coronavirus disease 2019 (COVID-19): A review. JAMA, 2020, 324(8), 782-793.
[http://dx.doi.org/10.1001/jama.2020.12839] [PMID: 32648899]
[4]
Zhou, P.; Yang, X.L.; Wang, X.G.; Hu, B.; Zhang, L.; Zhang, W.; Si, H.R.; Zhu, Y.; Li, B.; Huang, C.L.; Chen, H.D.; Chen, J.; Luo, Y.; Guo, H.; Jiang, R.D.; Liu, M.Q.; Chen, Y.; Shen, X.R.; Wang, X.; Zheng, X.S.; Zhao, K.; Chen, Q.J.; Deng, F.; Liu, L.L.; Yan, B.; Zhan, F.X.; Wang, Y.Y.; Xiao, G.F.; Shi, Z.L. A pneumonia outbreak associated with a new coronavirus of probable bat origin. Nature, 2020, 579(7798), 270-273.
[http://dx.doi.org/10.1038/s41586-020-2012-7] [PMID: 32015507]
[5]
Dong, N.; Yang, X.; Ye, L. Genomic and protein structure modelling analysis depicts the origin and infectivity of bioRxiv, 2019, 2020.01.20.913368.
[6]
Paraskevis, D.; Kostaki, E G; Magiorkinis, G. Full-genome evolutionary analysis of the novel corona virus(2019-nCoV) rejects the hypothesis of emergence as a result of a recent recombination event. Infection, genetics and Evolution. Infect. Genet. Evol., 2020, 79, 104212.
[7]
Fehr, A.R.; Perlman, S. Coronaviruses: An overview of their replication and pathogenesis. Methods Mol. Biol., 2015, 1282, 1-23.
[http://dx.doi.org/10.1007/978-1-4939-2438-7_1] [PMID: 25720466]
[8]
Jin, Z.; Du, X.; Xu, Y.; Deng, Y.; Liu, M.; Zhao, Y.; Zhang, B.; Li, X.; Zhang, L.; Peng, C.; Duan, Y.; Yu, J.; Wang, L.; Yang, K.; Liu, F.; Jiang, R.; Yang, X.; You, T.; Liu, X.; Yang, X.; Bai, F.; Liu, H.; Liu, X.; Guddat, L.W.; Xu, W.; Xiao, G.; Qin, C.; Shi, Z.; Jiang, H.; Rao, Z.; Yang, H. Structure of Mpro from SARS-CoV-2 and discovery of its inhibitors. Nature, 2020, 582(7811), 289-293.
[http://dx.doi.org/10.1038/s41586-020-2223-y] [PMID: 32272481]
[9]
Goyal, B.; Goyal, D. Targeting the dimerization of the main protease of coronaviruses: A potential broad-spectrum therapeutic strategy. ACS Comb. Sci., 2020, 22(6), 297-305.
[http://dx.doi.org/10.1021/acscombsci.0c00058] [PMID: 32402186]
[10]
Rathnayake, A.D.; Zheng, J.; Kim, Y.; Perera, K.D.; Mackin, S.; Meyerholz, D.K.; Kashipathy, M.M.; Battaile, K.P.; Lovell, S.; Perlman, S.; Groutas, W.C.; Chang, K.O. 3C-like protease inhibitors block coronavirus replication in vitro and improve survival in MERS-CoV-infected mice. Sci. Transl. Med., 2020, 12(557), eabc5332.
[http://dx.doi.org/10.1126/scitranslmed.abc5332] [PMID: 32747425]
[11]
Riccio, F.; Talapatra, S.K.; Oxenford, S.; Angell, R.; Mazzon, M.; Kozielski, F. Development and validation of RdRp Screen, a crystallization screen for viral RNA-dependent RNA polymerases. Biol. Open, 2019, 8(1), 1-47.
[http://dx.doi.org/10.1242/bio.037663] [PMID: 30602529]
[12]
Su, L.; Duan, X H Xu, WC Screening of anti-2019-nCoV inhibitors by taking RNA-dependent RNA polymerase as target. Chinese Archives of Traditional Chinese Medicine, 2020, 38(05), 7-13.
[13]
Huang, F.; Li, Y.; Leung, E.L.H.; Liu, X.; Liu, K.; Wang, Q.; Lan, Y.; Li, X.; Yu, H.; Cui, L.; Luo, H.; Luo, L. A review of therapeutic agents and Chinese herbal medicines against SARS-COV-2 (COVID-19). Pharmacol. Res., 2020, 158, 104929.
[http://dx.doi.org/10.1016/j.phrs.2020.104929] [PMID: 32442720]
[14]
Silva, L.R.; da Silva Santos-Júnior, P.F.; de Andrade Brandão, J.; Anderson, L.; Bassi, Ê.J.; Xavier de Araújo-Júnior, J.; Cardoso, S.H.; da Silva-Júnior, E.F. Druggable targets from coronaviruses for designing new antiviral drugs. Bioorg. Med. Chem., 2020, 28(22), 115745.
[http://dx.doi.org/10.1016/j.bmc.2020.115745] [PMID: 33007557]
[15]
Shyr, Z.A.; Gorshkov, K.; Chen, C.Z.; Zheng, W. Drug discovery strategies for SARS-CoV-2. J. Pharmacol. Exp. Ther., 2020, 375(1), 127-138.
[http://dx.doi.org/10.1124/jpet.120.000123] [PMID: 32723801]
[16]
Marshall, G.R.; Taylor, C.M. Introduction to computer-assisted drug design-overview and perspective for the future. Comprehensive Medicinal Chemistry II, 2007, 4, 13-41.
[http://dx.doi.org/10.1016/B0-08-045044-X/00241-8]
[17]
Usha, T.; Shanmugarajan, D.; Goyal, A.K.; Kumar, C.S.; Middha, S.K. Recent updates on computer-aided drug discovery: Time for a paradigm shift. Curr. Top. Med. Chem., 2017, 17(30), 3296-3307.
[http://dx.doi.org/10.2174/1568026618666180101163651] [PMID: 29295698]
[18]
Battisti, V.; Wieder, O.; Garon, A.; Seidel, T.; Urban, E.; Langer, T. A computational approach to identify potential novel inhibitors against the coronavirus SARS-CoV-2. Mol. Inform., 2020, 39(10), e2000090.
[http://dx.doi.org/10.1002/minf.202000090] [PMID: 32721082]
[19]
Gao, Y.; Yan, L; Huang, Y Structure of the RNA-dependent RNA polymerase from COVID-19 virus. Science, 2020, 368(6492), 779-782.
[20]
Liu, Y.; Tang, Z.; Wang, M. Potential SARS-COV-2 3CL protease inhibitors selection from TCMSP platform by molecular docking approach. Chin. Tradit. Herbal Drugs, 2020, 51(07), 1694-1703.
[21]
Lipinski, C.A.; Lombardo, F.; Dominy, B.W.; Feeney, P.J. Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Adv. Drug Deliv. Rev., 2001, 46(1-3), 3-26.
[http://dx.doi.org/10.1016/S0169-409X(00)00129-0] [PMID: 11259830]
[22]
Daina, A.; Michielin, O.; Zoete, V. SwissADME: A free web tool to evaluate pharmacokinetics, drug-likeness and medicinal chemistry friendliness of small molecules. Sci. Rep., 2017, 7(1), 42717.
[http://dx.doi.org/10.1038/srep42717] [PMID: 28256516]
[23]
Imran, M.; Kumar Arora, M.; Asdaq, S.M.B.; Khan, S.A.; Alaqel, S.I.; Alshammari, M.K.; Alshehri, M.M.; Alshrari, A.S.; Mateq Ali, A.; Al-Shammeri, A.M.; Alhazmi, B.D.; Harshan, A.A.; Alam, M.T. Abida, Discovery, development, and patent trends on molnupiravir: A prospective oral treatment for COVID-19. Molecules, 2021, 26(19), 5795.
[http://dx.doi.org/10.3390/molecules26195795] [PMID: 34641339]
[24]
Sarah, H; Indrasena, R.K; Shashi, K.T; Matthew, B.H; Alex, E.C; Shaobo, W; William, B; Davey, S; Aaron, FC; Mark, E; Tariq, MR Discovery and mechanism of SARS-CoV-2 main protease inhibitors. J. Med. Chem., 65(4), 2866-2879.
[http://dx.doi.org/10.1021/acs.jmedchem.1c00566]
[25]
Sang, H. H.; Christopher, M. G. Tarun, A Structure-based optimization of ML300-derived, noncovalent inhibitors targeting the severe acute respiratory syndrome coronavirus 3CL protease (SARS-CoV-2 3CLpro). J. Med. Chem., 65(4), 28820-28904.
[http://dx.doi.org/10.1021/acs.jmedchem.1c00598]
[26]
Naoya, K.; Michael, D S.; Chunlong, M. Expedited approach toward the rational design of noncovalent SARS-CoV-2 main protease inhibitors. J. Med. Chem., 65(4), 2848-2865.
[http://dx.doi.org/10.1021/acs.jmedchem.1c00509]
[27]
Ghosh, A.K.; Raghavaiah, J.; Shahabi, D.; Yadav, M.; Anson, B.J.; Lendy, E.K.; Hattori, S.I.; Higashi-Kuwata, N.; Mitsuya, H.; Mesecar, A.D. Indole chloropyridinyl ester-derived SARS-CoV-2 3CLpro inhibitors: Enzyme inhibition, antiviral efficacy, structure-activity relationship, and X-ray structural studies. J. Med. Chem., 2021, 64(19), 14702-14714.
[http://dx.doi.org/10.1021/acs.jmedchem.1c01214] [PMID: 34528437]
[28]
Durrant, J.D.; McCammon, J.A. Molecular dynamics simulations and drug discovery. BMC Biol., 2011, 9(1), 71.
[http://dx.doi.org/10.1186/1741-7007-9-71] [PMID: 22035460]
[29]
Hospital, A.; Goñi, J.R.; Orozco, M.; Gelpí, J.L. Molecular dynamics simulations: Advances and applications. Adv. Appl. Bioinform. Chem., 2015, 8, 37-47.
[PMID: 26604800]

Rights & Permissions Print Cite
Article Metrics
1
© 2024 Bentham Science Publishers | Privacy Policy