question: Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) has been the choice of recent studies worldwide to control its pandemic Given the similarity with the earlier SARS-CoV, it is possible to use the previously reported inhibitors to develop a new treatment for the current attack of SARS-CoV-2 This study used the formerly published SARS-CoV Mᵖʳᵒ small-molecule protease inhibitors to develop a pharmacophore model in order to design new ligands Several strategies and scaffolds were evaluated in silico giving rise to ten newly designed compounds Molecular docking and dynamics simulations were performed on Mᵖʳᵒ enzyme in its active site to evaluate the newly designed ligands I–X The results obtained from this work showed that compounds III–VI had a better molecular docking score than the co-crystallized ligand baicalein (3WL) giving −5 99, −5 94, −6 31, −6 56 and −5 74 kcal mol⁻¹, respectively Moreover, they could bind to the Mᵖʳᵒ binding site better than I, II and VII–X The most promising chromen-2-one based compounds V–VI had sufficiently acceptable physicochemical and ADMET properties to be considered new leads for further investigations This new understanding should help to improve predictions of the impact of new treatments on COVID-19