Ojeda-Montes_2018_Med.Res.Rev_38_1874

The inhibition of dipeptidyl peptidase-IV (DPP-IV) has emerged over the last decade as one of the most effective treatments for type 2 diabetes mellitus, and consequently (a) 11 DPP-IV inhibitors have been on the market since 2006 (three in 2015), and (b) 74 noncovalent complexes involving human DPP-IV and drug-like inhibitors are available at the Protein Data Bank (PDB). The present review aims to (a) explain the most important activity cliffs for DPP-IV noncovalent inhibition according to the binding site structure of DPP-IV, (b) explain the most important selectivity cliffs for DPP-IV noncovalent inhibition in comparison with other related enzymes (i.e., DPP8 and DPP9), and (c) use the information deriving from this activity/selectivity cliff analysis to suggest how virtual screening protocols might be improved to favor the early identification of potent and selective DPP-IV inhibitors in molecular databases (because they have not succeeded in identifying selective DPP-IV inhibitors with IC50