<p>In the absence of an approved vaccine, developing effective SARS-CoV-2 antivirals is essential to tackle the current pandemic health crisis due to the COVID-19 spread. As any traditional drug discovery program is a time-consuming and costly process requiring more than one decade to be completed, <i>in silico</i> repurposing of existing drugs is the preferred way for rapidly selecting promising clinical candidates. Herein we present a virtual screening campaign to identify covalent and

more »

... alent inhibitors of the SARS-CoV-2 papain-like protease (PLpro) showing potential multi-target activities for the COVID-19 treatment. A dataset including 688 phase III and 1702 phase IV clinical trial drugs was downloaded from ChEMBL (version 27.1) and docked to the recently released crystal structure of PLpro in complex with a covalently bound peptide inhibitor. The obtained results were analyzed by combining protein-ligand interaction fingerprint similarities, conventional docking scores and MMGBSA binding free energies and allowed the identification of some interesting candidates for further <i>in-vitro</i> testing. To the best of our knowledge, this study represents the first attempt to repurpose drugs for a covalent inhibition of PLpro and could pave the way for new therapeutic strategies against COVID-19.<b></b></p>