In silico evaluation of bisphosphonates identifies leading candidates for SARS-CoV-2 RdRp inhibition
Author Identifier
Seshadri Vasan: https://orcid.org/0000-0002-7326-3210
Document Type
Journal Article
Publication Title
Journal of Molecular Graphics and Modelling
Volume
136
Publisher
Elsevier
School
School of Medical and Health Sciences
RAS ID
77386
Funders
Birla Institute of Technology and Science, Pilani / University of York / Royal College of Physicians and Surgeons of Glasgow
Abstract
The novel coronavirus disease (COVID-19) pandemic has resulted in 777 million confirmed cases and over 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. Post Acute 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. In this study, we have investigated all bisphosphonates (BPs) on the ChEMBL database 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 in Japan with minodronate could be valuable.
DOI
10.1016/j.jmgm.2024.108939
Creative Commons License
This work is licensed under a Creative Commons Attribution-Noncommercial 4.0 License
Comments
Muzaffar-Ur-Rehman, M., Chougule, K. S., Chandu, A., Kuthe, P. V., Garg, M., Sankaranarayanan, M., & Vasan, S. S. (2025). In silico evaluation of bisphosphonates identifies leading candidates for SARS-CoV-2 RdRp inhibition. Journal of Molecular Graphics and Modelling, 136, 108939. https://doi.org/10.1016/j.jmgm.2024.108939