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Computationally repurposed drugs and natural products against RNA dependent RNA polymerase as potential COVID-19 therapies.

ABSTRACT: Repurposing of existing drugs and drug candidates is an ideal approach to identify new potential therapies for SARS-CoV-2 that can be tested without delay in human trials of infected patients. Here we applied a virtual screening approach using Autodock Vina and molecular dynamics simulation in tandem to calculate binding energies for repurposed drugs against the SARS-CoV-2 RNA-dependent RNA polymerase (RdRp). We thereby identified 80 promising compounds with potential activity against SARS-Cov2, consisting of a mixture of antiviral drugs, natural products and drugs with diverse modes of action. A substantial proportion of the top 80 compounds identified in this study had been shown by others to have SARS-CoV-2 antiviral effects in vitro or in vivo, thereby validating our approach. Amongst our top hits not previously reported to have SARS-CoV-2 activity, were eribulin, a macrocyclic ketone analogue of the marine compound halichondrin B and an anticancer drug, the AXL receptor tyrosine kinase inhibitor bemcentinib. Our top hits from our RdRp drug screen may not only have utility in treating COVID-19 but may provide a useful starting point for therapeutics against other coronaviruses. Hence, our modelling approach successfully identified multiple drugs with potential activity against SARS-CoV-2 RdRp.

Supplementary information

The online version contains supplementary material available at 10.1186/s43556-021-00050-3.

SUBMITTER: Piplani S

PROVIDER: S-EPMC8450033 | biostudies-literature | 2021

REPOSITORIES: biostudies-literature

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Computationally repurposed drugs and natural products against RNA dependent RNA polymerase as potential COVID-19 therapies.

Piplani Sakshi S Singh Puneet Kumar PK Winkler David A DA Petrovsky Nikolai N

Molecular biomedicine 20210920 1

Repurposing of existing drugs and drug candidates is an ideal approach to identify new potential therapies for SARS-CoV-2 that can be tested without delay in human trials of infected patients. Here we applied a virtual screening approach using Autodock Vina and molecular dynamics simulation in tandem to calculate binding energies for repurposed drugs against the SARS-CoV-2 RNA-dependent RNA polymerase (RdRp). We thereby identified 80 promising compounds with potential activity against SARS-Cov2, ...[more]

PMID: 34766004

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Project description:COVID-19, caused by Severe Acute Respiratory Syndrome Corona Virus 2, is declared a Global Pandemic by WHO in early 2020. In the present situation, though more than 180 vaccine candidates with some already approved for emergency use, are currently in development against SARS-CoV-2, their safety and efficacy data is still in a very preliminary stage to recognize them as a new treatment, which demands an utmost emergency for the development of an alternative anti-COVID-19 drug sine qua non for a COVID-19 free world. Since RNA-dependent RNA polymerase (RdRp) is an essential protein involved in replicating the virus, it can be held as a potential drug target. We were keen to explore the plant-based product against RdRp and analyze its inhibitory potential to treat COVID-19. A unique collection of 248 plant compounds were selected based on their antiviral activity published in previous literature and were subjected to molecular docking analysis against the catalytic sub-unit of RdRp. The docking study was followed by a pharmacokinetics analysis and molecular dynamics simulation study of the selected best-docked compounds. Tellimagrandin I, SaikosaponinB2, Hesperidin and (-)-Epigallocatechin Gallate were the most prominent ones that showed strong binding affinity toward RdRp. All the compounds mentioned showed satisfactory pharmacokinetics properties and remained stabilized at their respective binding sites during the Molecular dynamics simulation. Additionally, we calculated the free-binding energy/the binding properties of RdRp-ligand complexes with the connection of MM/GBSA. Interestingly, we observe that SaikosaponinB2 gives the best binding affinity (∆Gbinding = -42.43 kcal/mol) in the MM/GBSA assay. Whereas, least activity is observed for Hesperidin (∆Gbinding = -22.72 kcal/mol). Overall our study unveiled the feasibility of the SaikosaponinB2 to serve as potential molecules for developing an effective therapy against COVID-19 by inhibiting one of its most crucial replication proteins, RdRp.

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Computationally repurposed drugs and natural products against RNA dependent RNA polymerase as potential COVID-19 therapies.

Supplementary information

Publications

Computationally repurposed drugs and natural products against RNA dependent RNA polymerase as potential COVID-19 therapies.

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