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

TL;DR

This study uses computational docking and molecular dynamics to identify existing drugs and natural products as potential inhibitors of SARS-CoV-2 RNA-dependent RNA polymerase, facilitating rapid COVID-19 therapy development.

Contribution

It combines docking and MD simulations to identify promising RdRP inhibitors among repurposed drugs and natural products for COVID-19 treatment.

Findings

Identified top 80 drug candidates with high affinity for RdRP.

Many predicted inhibitors have prior in vitro activity or predictions.

Provided a list of novel potential RdRP inhibitors for further testing.

Abstract

For fast development of COVID-19, it is only feasible to use drugs (off label use) or approved natural products that are already registered or been assessed for safety in previous human trials. These agents can be quickly assessed in COVID-19 patients, as their safety and pharmacokinetics should already be well understood. Computational methods offer promise for rapidly screening such products for potential SARS-CoV-2 activity by predicting and ranking the affinities of these compounds for specific virus protein targets. The RNA-dependent RNA polymerase (RdRP) is a promising target for SARS-CoV-2 drug development given it has no human homologs making RdRP inhibitors potentially safer, with fewer off-target effects that drugs targeting other viral proteins. We combined robust Vina docking on RdRP with molecular dynamic (MD) simulation of the top 80 identified drug candidates to yield a list of the most promising RdRP inhibitors. Literature reviews revealed that many of the predicted inhibitors had been shown to have activity in in vitro assays or had been predicted by other groups to have activity. The novel hits revealed by our screen can now be conveniently tested for activity in RdRP inhibition assays and if conformed testing for antiviral activity invitro before being tested in human trials