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In silico evaluation of bisphosphonates identifies leading candidates for SARS-CoV-2 RdRp inhibition
Mohammed Muzaffar-Ur-Rehman1, Kishor Suryakant Chougule1, Ala Chandu1
1Department of Pharmacy, Birla Institute of Technology and Science, Pilani, 333031, India.
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.
Insights
Bisphosphonates show potential for treating COVID-19 and Long COVID by inhibiting the SARS-CoV-2 NiRAN domain. Further studies on drugs like minodronate could reveal new therapeutic options.
Area of Science:
- Computational drug discovery
- Virology
- Pharmacology
Background:
- The COVID-19 pandemic caused millions of deaths globally, with limited treatment options.
- Post-Acute Sequelae of SARS-CoV-2 infection (PASC), or Long COVID, also lacks effective treatments.
- Current treatments include remdesivir and nirmatrelvir/ritonavir, but new therapeutic agents are urgently needed.
Purpose of the Study:
- To identify potential therapeutic agents for COVID-19 and PASC by investigating bisphosphonates (BPs).
- To explore the competitive binding of BPs to the nidovirus RNA-dependent RNA polymerase (RdRp)-associated nucleotidyl transferase (NiRAN) domain.
- To provide an in silico mechanistic basis for observed reduced COVID-19 incidence in users of certain BPs.
Main Methods:
- Systematic investigation of bisphosphonates from the ChEMBL database.
- In silico analysis including molecular docking and molecular dynamics to assess binding to the NiRAN domain.
- Selection of seven candidate bisphosphonates based on binding affinity and resemblance to approved drugs.
Main Results:
- Seven bisphosphonates were identified as potential binders to the SARS-CoV-2 NiRAN domain.
- Two candidates closely resemble approved drugs minodronate and zoledronate.
- The study provides an in silico explanation for reduced SARS-CoV-2 testing, diagnosis, and hospitalization rates in alendronate and zoledronate users.
Conclusions:
- Bisphosphonates represent a promising class of compounds for developing novel COVID-19 and PASC treatments.
- The NiRAN domain is a viable target for antiviral drug development.
- Further observational studies, particularly in Japan with minodronate, are warranted to validate these findings.
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