Integrated Synthetic, Biophysical, and Computational Investigations of Covalent Inhibitors of Prolyl Oligopeptidase and Fibroblast Activation Protein α

Over
the past decade, there has been increasing interest in covalent
inhibition as a drug design strategy. Our own interest in the development
of prolyl oligopeptidase (POP) and fibroblast activation protein α
(FAP) covalent inhibitors has led us to question whether these two
serine proteases were equal in terms of their reactivity toward electrophilic
warheads. To streamline such investigations, we exploited both computational
and experimental methods to investigate the influence of different
reactive groups on both potency and binding kinetics using both our
own series of POP inhibitors and others’ discovered hits. A
direct correlation between inhibitor reactivity and residence time
was demonstrated through quantum mechanics methods and further supported
by experimental studies. This computational method was also successfully
applied to FAP, as an overview of known FAP inhibitors confirmed our
computational predictions that more reactive warheads (e.g., boronic
acids) must be employed to inhibit FAP than for POP.