Transmembrane serine protease 2 (TMPRSS2) has been established as one of the host proteins that facilitate entry of coronaviruses into host cells . One of the approaches often employed towards preventing the entry and proliferation of viruses is computer-aided inhibition studies to identify potent compounds that can inhibit activity of viral targets in the host through binding at the active site . In this study, we developed a pharmacophore model of reportedly potent drugs against severe acute respiratory syndrome coronaviruses 1 and 2 (SARS-CoV-1 and -2). The model was used to screen the ZINC database for commercially available compounds having similar features with the experimentally tested drugs . The top 3000 compounds retrieved were docked into the active sites of a homology-modelled TMPRSS2 . Docking scores of the top binders were validated and the top-ranked compounds were subjected to ADME, Lipinski's and medicinal Chemistry property predictions for druglikeness analyses . Two lead compounds, ZINC64606047 and ZINC05296775, were identified having binding affinities higher than those of the reference inhibitors, favorable interactions with TMPRSS2 active site residues and good ADME and medicinal chemistry properties . Molecular dynamics simulation was used to assess the stability and dynamics of the interactions of these compounds with TMPRSS2 . Binding free energy and contribution energy evaluations were determined using MMPBSA method . Analyses of the trajectory dynamics collectively established further that the lead compounds bound and interacted stably with active site residues of TMPRSS2 . Nonetheless, experimental studies are needed to further assess the potentials of these compounds as possible therapeutics against coronaviruses . Communicated by Ramaswamy H. Sarma.