Repurposing drugs for treatment of SARS-CoV-2 infection: computational design insights into mechanisms of action

Abstract

The COVID-19 pandemic has negatively affected human life globally. It has led to economic crises and health emergencies across the world, spreading rapidly among the human population and has caused many deaths. Currently, there are no treatments available for COVID-19 so there is an urgent need to develop therapeutic interventions that could be used against the novel coronavirus infection. In this research, we used computational drug design technologies to repurpose existing drugs as inhibitors of SARS-CoV-2 viral proteins. The Broad Institute’s Drug Repurposing Hub consists of in-development/approved drugs and was computationally screened to identify potential hits which could inhibit protein targets encoded by the SARS-CoV-2 genome. By virtually screening the Broad collection, using rationally designed pharmacophore features, we identified molecules which may be repurposed against viral nucleocapsid and non-structural proteins. The pharmacophore features were generated after careful visualisation of the interactions between co-crystalised ligands and the protein binding site. The ChEMBL database was used to determine the compound’s level of inhibition of SARS-CoV-2 and correlate the predicted viral protein target with whole virus in vitro data. The results from this study may help to accelerate drug development against COVID-19 and the hit compounds should be progressed through further in vitro and in vivo studies on SARS-CoV-2.

Graphical Abstract

Communicated by Ramaswamy H. Sarma

Keywords:

• SARS-CoV-2
• COVID-19
• drug repurposing
• pharmacophore
• virtual screening
• nucleocapsid protein
• non-structural proteins

Acknowledgements

The Trinity Biomedical Sciences Institute (TBSI) is supported by a capital infrastructure investment from Cycle 5 of the Irish Higher Education Authority’s Programme for Research in Third Level Institutions (PRTLI). We thank the software vendors for their continuing support of academic research efforts, in particular the contributions of the Chemical Computing Group, Biovia and OpenEye Scientific. The support and provisions of Dell Ireland is also acknowledged. The Trinity College Dublin MSc in Molecular Medicine is also gratefully acknowledged for supporting this work.

Disclosure statement

The authors report no potential conflicts of interest.