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Yin, Y. H., & Yin-Quan, T. (2022). Computational Screening of Repurposed Drugs Targeting Sars-Cov-2 Main Protease By Molecular Docking. Sudan Journal of Medical Sciences (SJMS), 17(3), 387–400. https://doi.org/10.18502/sjms.v17i3.12125
https://doi.org/10.18502/sjms.v17i3.12125
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Yow Hui Yin
Yow Hui Yin
School of Pharmacy, Faculty of Health and Medical Sciences Taylor’s University, Subang Jaya, Malaysia
-
Tang Yin-Quan
Tang Yin-Quan
Centre for Drug Discovery and Molecular Pharmacology (CDDMP), Faculty of Health and Medical Sciences, Taylor’s University, Subang Jaya, Malaysia
Published Date
- Sep 30, 2022
Computational Screening of Repurposed Drugs Targeting Sars-Cov-2 Main Protease By Molecular 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.
Keywords:
repurposed drug, COVID-19, Mpro, docking
References
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[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
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[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 COVID- 19 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-CoV- 2: 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
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