The type II transmembrane serine protease TMPRSS2 facilitates the entry of coronaviruses, such as SARS-CoV-2, into host cells by cleaving the S1/S2 interface of the viral spike protein . Based on structural data derived from X-ray crystallographic data of related trypsin-like proteases, a homology model of TMPRSS2 is described and validated using the broad spectrum COVID-19 drug candidate camostat as a probe . Both active site recognition and catalytic function are examined using quantum mechanics/molecular mechanics molecular dynamic (QM/MM MD) simulations of camostat and its active metabolite , 4- (4-guanidinobenzoyloxy) phenylacetate (GBPA). Substrate binding is shown to be primarily stabilized through salt bridge formation between the shared guanidino pharmacophore and D435 in pocket A (flanking the catalytic S441). Based on the binding mode of GBPA, residues K342 and W461 have been identified as potential contacts involved in TMPRSS2 selective binding and activity . Additional data is reported that indicates the transition state structure is stabilized through H-bonding interactions with the backbone N-H groups within an oxyanion hole following bottom-side attack of the carbonyl by S441 . This is supported by prior work on related serine proteases suggesting further strategies to exploit in the design of more potent inhibitors . Taken overall, the proposed structure along with the key contact sites and mechanistic features identified should prove highly advantageous to the design and rational development of safe and effective therapeutics that target TMPRSS2 and avoid inhibition of other trypsin-dependent processes.