The non-covalent, carbonitrile, and boronic ester/acid bicyclic series were tested in vitro for inhibition of POP activity. The results of these assays can be found in Table . The bicyclic boronic ester pro-drugs showed very potent in vitro activity against POP, with N-Cbz bicycles 10c and 12a exhibiting low single-digit nanomolar potency. This high inhibitor activity was predicted by the promising docking pose (Figure /D) in which all three key ligandprotein interactions are fulfilled. Unexpectedly, the N-Boc derivative 10e displayed similar potency. Although the benzyl group is missing for aromatic interactions with Phe173, the large, greasy Boc protecting group might be compensating for this loss. The acetyl derivative 10d exhibited low micromolar activity, likely attributed to the lack of a large N-bound group to stabilize the inhibitor in the active site. The free amine boronic acid derivative 10f exhibited submicromolar potency in POP. This activity can likely be attributed to the assay conditions; the pH 8.0 basic buffer likely renders the amine neutral and allows it to act as a hydrogen bond acceptor to interact with Arg643. While, in general, nitrile and boronic acids are somewhat equipotent, boronic acids are likely to exhibit longer residence times in the active sites, making them more suitable drug candidates. As observed previously by our group, it is likely that the nitrile is not properly oriented to react covalently with the catalytic serine in POP, and therefore binds non-covalently.