Translations:Discovery and development of dipeptidyl peptidase-4 inhibitors/16/en

Fig.3: The key interactions between the ligand and DPP-4 complex. The ligand's basic amine forms a hydrogen bonding network. The nitrile reacts with the catalytic active serine and forms an imidate adduct

DPP-4 inhibitors usually have an electrophilic group that can interact with the hydroxyl of the catalytic serine in the active binding site (Figure 3). Frequently that group is a nitrile group but can also be boronic acid or diphenyl phosphonate. This electrophilic group can bind to the imidate complex with covalent bonds and slow, tight-binding kinetics but this group is also responsible for stability issues due to reactions with the free amino group of the P2-amino acid. Therefore, inhibitors without the electrophilic group have also been developed, but these molecules have shown toxicity due to affinity to other dipeptidyl peptidases, e.g. DPP-2, DPP-8 and DPP-9.