An efficient treatment against a COVID-19 disease, caused by the novel coronavirus SARS-CoV-2 (CoV2), remains a challenge. The papain-like protease (PL^pro) from the human coronavirus is a protease that plays a critical role in virus replication. Moreover, CoV2 uses this enzyme to modulate the host’s immune system to its own benefit. Therefore, it represents a highly promising target for the development of antiviral drugs. We used Approximate Bayesian Computation tools, molecular modelling and enzyme activity studies to identify highly active inhibitors of the PL^pro. We discovered organoselenium compounds, ebselen and its structural analogues, as a novel approach for inhibiting the activity of PL^proCoV2. Furthermore, we identified, for the first time, inhibitors of PL^proCoV2 showing potency in the nanomolar range. Moreover, we found a difference between PL^pro from SARS and CoV2 that can be correlated with the diverse dynamics of their replication, and, putatively to disease progression.