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

Sakshi Piplani,Puneet Kumar Singh,David A Winkler,Nikolai Petrovsky

doi:10.1186/s43556-021-00050-3

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.

Highlights

severe acute respiratory syndrome (SARS)-CoV-2 is the virus responsible for the COVID-19 pandemic that first appeared in 2019 and has caused major morbidity and mortality worldwide
RNA-dependent RNA polymerase (RdRp) ligand docking followed by molecular dynamics simulations Many computational studies have attempted to predict which existing drugs may inhibit the SARS-CoV-2 main protease, Mpro, but far fewer studies have targeted the viral polymerase, RdRp
The RdRp binding free energies for the top 80 hits (Supplementary Table S1) as calculated by either of two methods correlated very well (r2 = 0.84), and the free energies calculated by the thermodynamic cycle correlated with the Vina docking scores (r2 = 0.64)

Summary

Introduction

SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) is the virus responsible for the COVID-19 pandemic that first appeared in 2019 and has caused major morbidity and mortality worldwide. Recent work demonstrated the ability to undertake computational de novo drug design based on the recently identified structure of Mpro, the main SARS-CoV-2 protease [1]. Another interesting but less studied target for SARS-CoV-2 drug development is its RNA-dependent RNA polymerase (RdRp). After host cell infection viral RdRp participates in formation of the molecular machinery for genome replication by complexing with other transcription factors. It initiates and regulates the elongation of the RNA strand, which involves the addition of hundreds to thousands of nucleotides. When incorporated into the newly synthesised RNA chain, nucleotide analogues, such as remdesivir, will block the RNA elongation catalysed by RdRp

Methods

Results

Conclusion