Furthermore, in both POP and FAP, the boronic acid motif may act as a transition state analogue, forming both hydrogen bonds (with His680 and Tyr473 and with His734 and Tyr571, respectively) and covalent bonds with the catalytic triad (Ser554 and Ser624, respectively) in a tetrahedral configuration, as opposed to the trigonal planar configuration conferred by nitrilecontaining inhibitors (Figure ). Nonetheless, the design of FAP/POP dual inhibitors remains challenging due to the difference in polarity between the active sites. While three hydrophobic or hydrogen bond donor residues contribute the necessary interactions for high inhibition of POP (aromatic interactions with Phe173 and hydrogen bonding with Trp595 and Arg643), high inhibition of FAP relies on interaction with hydrogen bond acceptors Glu203 and Glu204 in the hydrophilic pocket (Figure ). n.b. the hydrolyzed boronic esters (boronic acids) were docked.