Computational Screening of Repurposed Drugs Targeting Sars-Cov-2 Main Protease By Molecular Docking
Keywords:
repurposed drug, COVID-19, Mpro, docking
Abstract
Background: COVID-19 (Coronavirus disease 2019) is caused by the severe acute
respiratory syndrome coronavirus type 2 (SARS-CoV-2), which poses significant global
health and economic crisis that urges effective treatment.
Methods: A total of 11 molecules (baricitinib, danoprevir, dexamethasone, hydroxychloroquine, ivermectin, lopinavir, methylprednisolone, remdesivir, ritonavir and
saridegib, ascorbic acid, and cepharanthine) were selected for molecular docking
studies using AutoDock VINA to study their antiviral activities via targeting SARS-CoV’s
main protease (Mpro), a cysteine protease that mediates the maturation cleavage of
polyproteins during virus replication.
Results: Three drugs showed stronger binding affinity toward Mpro than N3 (active
Mpro inhibitor as control): danoprevir (–7.7 kcal/mol), remdesivir (–8.1 kcal/mol), and
saridegib (–7.8 kcal/mol). Two primary conventional hydrogen bonds were identified in
the danoprevir-Mpro complex at GlyA:143 and GlnA:189, whereas the residue GluA:166
formed a carbon–hydrogen bond. Seven main conventional hydrogen bonds were
identified in the remdesivir at AsnA:142, SerA:144, CysA:145, HisA:163, GluA:166,
and GlnA:189, whereas two carbon–hydrogen bonds were formed by the residues
HisA:41 and MetA:165. Cepharanthine showed a better binding affinity toward Mpro
(–7.9 kcal/mol) than ascorbic acid (–5.4 kcal/mol). Four carbon–hydrogen bonds were
formed in the cepharanthine-Mpro complex at HisA:164, ProA;168, GlnA;189, and
ThrA:190.
Conclusion: The findings of this study propose that these drugs are potentially
inhibiting the SAR-CoV-2 virus by targeting the Mpro protein
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Guilliams, T., Latimer, J., McNamee, C., Norris, A., Sanseau, P., Cavalla, D., & Pirmohamed, M. (2019). Drug repurposing: Progress, challenges and recommendations.
Nature Reviews. Drug Discovery, 18, 41–58. https://doi.org/10.1038/nrd.2018.168
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COVID-19 - Efficacy, limitations, and challenges. Life Sciences, 259, 118275.
https://doi.org/10.1016/j.lfs.2020.118275
[8] Zhang, S. (2011). Computer-aided drug discovery and development. Drug Design
and Discovery, 716, 23–38. https://doi.org/10.1007/978-1-61779-012-6_2
[9] Wang, M.-Y., Zhao, R., Gao, L.-J., Gao, X.-F., Wang, D.-P., & Cao, J.-
M. (2020). SARS-CoV-2: Structure, biology, and structure-based therapeutics
development. Frontiers in Cellular and Infection Microbiology, 10, 587269.
https://doi.org/10.3389/fcimb.2020.587269
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Bhattacharyya, A., Kumar, H., Bansal, S., & Medhi, B. (2020). Drug targets for
corona virus: A systematic review. Indian Journal of Pharmacology, 52, 56–65.
https://doi.org/10.4103/ijp.IJP_115_20
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chymotrypsin-like protease inhibitors of SARS-CoV-2 via integrated computational
approach. Journal of Biomolecular Structure & Dynamics, 39, 2607–2616.
https://doi.org/10.1080/07391102.2020.1751298
[12] 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, H. (2020). Structure of Mpro from SARS-CoV-2 and discovery of its inhibitors.
Nature, 582, 289–293. https://doi.org/10.1038/s41586-020-2223-y
[13] Lovell, S. C., Davis, I. W., Arendall, W. B., III, de Bakker, P. I. W., Word, J.
M., Prisant, M. G., Richardson, J. S., & Richardson, D. C. (2003). Structure
validation by Calpha geometry: Phi,ψ and Cbeta deviation. Proteins, 50, 437–450.
https://doi.org/10.1002/prot.10286
[14] Trott, O., Olson, A. J. J. (2010). AutoDock Vina: Improving the speed and accuracy
of docking with a new scoring function, efficient optimization, and multithreading.
Journal of Computational Chemistry, 31(2), 455-461.
[15] Dassault Systemes. (2017). BIOVIA. BIOVIA Discovery Studio Visualizer.
[16] Huynh, T., Wang, H., Luan, B. (2020). In silico exploration of the molecular mechanism
of clinically oriented drugs for possibly inhibiting SARS-CoV-2’s main protease.
Journal of Physical Chemistry Letters, 11(11), 4413–4420.
[17] Kanhed, A. M., Patel, D. V., Teli, D. M., Patel, N. R., Chhabria, M. T., Yadav, M.R.J.M.d.
(2021). Identification of potential Mpro inhibitors for the treatment of COVID-19 by
using systematic virtual screening approach. Molecular Diversity, 25(1), 383–401.
[18] Jeffrey, G. A., & Saenger, W. (2012). Hydrogen bonding in biological structures.
Springer Science & Business Media.
[19] Meyer, E. E., Rosenberg, K. J., Israelachvili, J. (2006). Recent progress in
understanding hydrophobic interactions. PNAS, 103(43), 15739–15746.
[20] Harisna, A. H., Nurdiansyah, R., Syaifie, P. H., Nugroho, D. W., Saputro, K. E.,
Firdayani., Prakoso, C. D., Rochman, N. T., Maulana, N. N., Noviyanto, A., & Mardliyati,
E. (2021). In silico investigation of potential inhibitors to main protease and spike
protein of SARS-CoV-2 in propolis. Biochemistry and Biophysics Reports, 26,
100969. https://doi.org/10.1016/j.bbrep.2021.100969
[21] Kumar, K., Woo, S. M., Siu, T., Cortopassi, W. A., Duarte, F., & Paton, R. S. (2018).
Cation-π interactions in protein-ligand binding: Theory and data-mining reveal
different roles for lysine and arginine. Chemical Science (Cambridge), 9, 2655–
2665. https://doi.org/10.1039/C7SC04905F
[22] Ferreira de Freitas, R., & Schapira, M. (2017). A systematic analysis of
atomic protein-ligand interactions in the PDB. MedChemComm, 8, 1970–1981.
https://doi.org/10.1039/C7MD00381A
[23] Miao, M., Jing, X., De Clercq, E., & Li, G. (2020). Danoprevir for the treatment of
hepatitis C virus infection: Design, development, and place in therapy. Drug Design,
Development and Therapy, 14, 2759–2774. https://doi.org/10.2147/DDDT.S254754
[24] Hosseini, F. S., & Amanlou, M. (2020). Simeprevir, potential candidate to
repurpose for coronavirus infection: Virtual screening and molecular docking study.
Preprint.org. https://www.preprints.org/manuscript/202002.0438/v1
[25] da Costa, L. J., Pereira, M. M., de Souza Ramos, L., de Mello, T. P., Silva, L.
N., Branquinha, M. H., & Dos Santos, A. L. S. (2021). Protease Inhibitors as
Promising Weapons against COVID-19: Focus on repurposing of drugs used to
treat HIV and HCV infections. Current Topics in Medicinal Chemistry, 21, 1429–1438.
https://doi.org/10.2174/1568026621666210701093407
[26] Chen, H., Zhang, Z., Wang, L., Huang, Z., Gong, F., Li, X., Chen, Y., & Wu, J. J.
(2020). First clinical study using HCV protease inhibitor danoprevir to treat COVID19 patients. Medicine, 99, e23357. https://doi.org/10.1097/MD.0000000000023357
[27] Vangeel, L., Chiu, W., De Jonghe, S., Maes, P., Slechten, B., Raymenants, J., André,
E., Leyssen, P., Neyts, J., & Jochmans, D. (2022). Remdesivir, Molnupiravir and Nirmatrelvir remain active against SARS-CoV-2 Omicron and other variants of concern.
Antiviral Research, 198, 105252. https://doi.org/10.1016/j.antiviral.2022.105252
[28] Kokic, G., Hillen, H. S., Tegunov, D., Dienemann, C., Seitz, F., Schmitzova, J.,
Farnung, L., Siewert, A., Höbartner, C., & Cramer, P. (2021). Mechanism of
SARS-CoV-2 polymerase stalling by remdesivir. Nature Communications, 12, 279.
https://doi.org/10.1038/s41467-020-20542-0
[29] Naik, V. R., Munikumar, M., Ramakrishna, U., Srujana, M., Goudar, G., Naresh, P.,
Kumar, B. N., & Hemalatha, R. (2021). Remdesivir (GS-5734) as a therapeutic option
of 2019-nCOV main protease - In silico approach. Journal of Biomolecular Structure
& Dynamics, 39, 4701–4714. https://doi.org/10.1080/07391102.2020.1781694
[30] Nguyen, H. L., Thai, N. Q., Truong, D. T., & Li, M. S. (2020). Remdesivir strongly
binds to both RNA-dependent RNA polymerase and main protease of SARS-CoV2: Evidence from molecular simulations. The Journal of Physical Chemistry B, 124,
11337–11348. https://doi.org/10.1021/acs.jpcb.0c07312
[31] Beigel, J. H., Tomashek, K. M., Dodd, L. E., Mehta, A. K., Zingman, B. S., Kalil, A. C.,
Hohmann, E., Chu, H. Y., Luetkemeyer, A., Kline, S., Lopez de Castilla, D., Finberg, R.
W., Dierberg, K., Tapson, V., Hsieh, L., Patterson, T. F., Paredes, R., Sweeney, D. A.,
Short, W. R., … Lane, H. C., & the ACTT-1 Study Group Members. (2020). Remdesivir
for the treatment of Covid-19 - Final report. The New England Journal of Medicine,
383, 1813–1826. https://doi.org/10.1056/NEJMoa2007764
[32] Smelkinson, M. G. (2017). The Hedgehog signaling pathway emerges as a pathogenic
target. Journal of Developmental Biology, 5, 14. https://doi.org/10.3390/jdb5040014
[33] Baratella, E., Bussani, R., Zanconati, F., Marrocchio, C., Fabiola, G., Braga, L., Maiocchi,
S., Berlot, G., Volpe, M. C., Moro, E., Confalonieri, P., Cova, M. A., Confalonieri, M.,
Salton, F., & Ruaro, B. (2021). Radiological-pathological signatures of patients with
COVID-19-related pneumomediastinum: Is there a role for the Sonic hedgehog and
Wnt5a pathways? ERJ Open Research, 7, 7. https://doi.org/10.1183/23120541.00346-
2021
[34] Lee, M. J., Hatton, B. A., Villavicencio, E. H., Khanna, P. C., Friedman, S. D.,
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Published
2022-10-04
Section
Review article
