A second molecular docking campaign was conducted against TMPRSS2 when its crystal structure became available. Using the Zinc-22 library , this docking screen identified hit compounds '2222 and '2602 which were predicted to bind within the TMPRSS2 S1. We did not acquire a TMPRSS2 cocrystal structure with the '2222/'2602 compounds during this study. We instead validated the molecular interactions predicted from the docking using biophysical assays and showed that the TMPRSS2 S1 is critical for binding (likely mediated through the TMPRSS2 S436 residue), and the TMPRSS2 S441 residue is necessary for Hbonding. In total, 9/17 TTSPs contain the S436 residue within S1 (Extended Data Fig. ). Furthermore, this Ser residue is uncommon amongst human plasma proteases, with only plasmin and FVIIa possessing Ser whereas thrombin, activated Protein C and FXa have an Ala residue at this position (Extended Data Fig. ). This subclassification of trypsin-like serine proteases has been noted before and has enabled some trypsin-like serine protease selectivity through substituted benzamidine small molecule inhibitors .