A multi-stage virtual screening of FDA-approved drugs reveals potential inhibitors of SARS-CoV-2 main protease

Abstract

Coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is an ongoing global health emergency. Repurposing of approved pharmaceutical drugs for COVID-19 treatment represents an attractive approach to quickly identify promising drug candidates. SARS-CoV-2 main protease (M^pro) is responsible for the maturation of viral functional proteins making it a key antiviral target. Based on the recently revealed crystal structures of SARS-CoV-2 M^pro, we herein describe a multi-stage virtual screening protocol including pharmacophore screening, molecular docking and protein-ligand interaction fingerprints (PLIF) post-docking filtration for efficient enrichment of potent SARS-CoV-2 M^pro inhibitors. Potential hits, along with a cocrystallized control were further studied via molecular dynamics. A 150-ns production trajectory was followed by RMSD, free energy calculation, and H-bond analysis for each compound. The applied virtual screening protocol led to identification of five FDA-approved drugs with promising binding modes to key subsites of the substrate-binding pocket of SARS-CoV-2 M^pro. The identified compounds belong to different pharmaceutical classes, including several protease inhibitors, antineoplastic agents and a natural flavonoid. The drug candidates discovered in this study present a potential extension of the recently reported SARS-CoV-2 M^pro inhibitors that have been identified using other virtual screening protocols and may be repurposed for COVID-19 treatment.

Keywords:

• COVID-19
• SARS-CoV-2 main protease
• drug repurposing
• virtual screening
• pharmacophore
• docking
• MD simulations

Acknowledgements

This research was enabled in part by support provided by Westgrid (www.westgrid.ca) and Compute/Calcul Canada (www.computecanada.ca). Access to Westgrid was provided through collaboration with Professor Alex Brown, University of Alberta. We also thank Dr. Ahmed Taha Ayoub for helpful discussions and useful insights on the MD part of the study.

Disclosure statement

The authors declare no conflict of interest.

Data availability statement

All data are within the manuscript and the supplementary materials.