Version 1
: Received: 25 November 2023 / Approved: 27 November 2023 / Online: 27 November 2023 (16:52:17 CET)
Version 2
: Received: 27 December 2023 / Approved: 28 December 2023 / Online: 28 December 2023 (13:51:47 CET)
Version 3
: Received: 23 February 2024 / Approved: 26 February 2024 / Online: 26 February 2024 (13:51:28 CET)
How to cite:
Mohammed, M.; Chougule, K.S.; Ala, C.; Kuthe, P.V.; Garg, M.; Sankaranarayanan, M.; Vasan, S.S. On Bisphosphonates and COVID-19: In Silico Model Suggests Inhibition of SARS-CoV-2 RdRp as Potential Explanation. Preprints2023, 2023111727. https://doi.org/10.20944/preprints202311.1727.v3
Mohammed, M.; Chougule, K.S.; Ala, C.; Kuthe, P.V.; Garg, M.; Sankaranarayanan, M.; Vasan, S.S. On Bisphosphonates and COVID-19: In Silico Model Suggests Inhibition of SARS-CoV-2 RdRp as Potential Explanation. Preprints 2023, 2023111727. https://doi.org/10.20944/preprints202311.1727.v3
Mohammed, M.; Chougule, K.S.; Ala, C.; Kuthe, P.V.; Garg, M.; Sankaranarayanan, M.; Vasan, S.S. On Bisphosphonates and COVID-19: In Silico Model Suggests Inhibition of SARS-CoV-2 RdRp as Potential Explanation. Preprints2023, 2023111727. https://doi.org/10.20944/preprints202311.1727.v3
APA Style
Mohammed, M., Chougule, K.S., Ala, C., Kuthe, P.V., Garg, M., Sankaranarayanan, M., & Vasan, S.S. (2024). On Bisphosphonates and COVID-19: In Silico Model Suggests Inhibition of SARS-CoV-2 RdRp as Potential Explanation. Preprints. https://doi.org/10.20944/preprints202311.1727.v3
Chicago/Turabian Style
Mohammed, M., Murugesan Sankaranarayanan and Seshadri S Vasan. 2024 "On Bisphosphonates and COVID-19: In Silico Model Suggests Inhibition of SARS-CoV-2 RdRp as Potential Explanation" Preprints. https://doi.org/10.20944/preprints202311.1727.v3
Abstract
The novel coronavirus disease (COVID-19) pandemic has resulted in over 720 million confirmed cases and 7 million deaths worldwide, with insufficient treatment options. Innumerable efforts are being made around the world for faster identification of therapeutic agents to treat the deadly disease. Postacute sequelae of SARS-CoV-2 infection or COVID-19 (PASC), also called Long COVID, is still being understood and lacks treatment options as well. A growing list of drugs are being suggested by various in silico, in vitro and ex vivo models, however currently only two treatment options are widely used: the RNA-dependent RNA polymerase (RdRp) inhibitor remdesivir, and the main protease inhibitor nirmatrelvir in combination with ritonavir. Computational drug development tools and in silico studies involving molecular docking, molecular dynamics, entropy calculations and pharmacokinetics can be useful to identify new targets to treat COVID-19 and PASC, as shown in this work and our recent paper that identified alendronate as a promising candidate. We have now investigated all bisphosphonates which can bind competitively to nidovirus RdRp-associated nucleotidyl (NiRAN) transferase domain, and systematically down selected seven candidates (CHEMBL608526, CHEMBL196676, CHEMBL164344, CHEMBL4291724, CHEMBL4569308, CHEMBL387132, CHEMBL98211),two of which closely resemble the approved drugs minodronate and zoledronate. This work and our recent paper together provide an in silico mechanistic explanation for alendronate and zoledronate users having dramatically reduced odds of SARS-CoV-2 testing, COVID-19 diagnosis, and COVID-19-related hospitalizations, and indicate that similar observational studies with minodronate could be valuable.
Chemistry and Materials Science, Medicinal Chemistry
Copyright:
This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
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