Structure–Activity Relationship Analysis of Cocrystallized Gliptin-like Pyrrolidine, Trifluorophenyl, and Pyrimidine-2,4-Dione Dipeptidyl Peptidase‑4 Inhibitors

Approved
and potent reported dipeptidyl peptidase-4 (DPP-4) inhibitors
with gliptin-like structures are classified here according to their
structures and mechanisms of the inhibition in three groups: (i) those
with pyrrolidine or analogs as P1 fragment with α-aminoacyl
linker, (ii) structures with trifluorophenyl moiety or analogs as
P1 fragment with β-aminobutanoyl linker, and (iii) DPP-4 inhibitors
with pyrimidine-2,4-dione or analogs as P1′ fragment. The structure–activity
relationship analysis was performed for those whose cocrystallized
structures with the enzyme were published. While inhibitors with pyrrolidine
and trifluorophenyl moiety or analogs as P1 fragment bind in a similar
way in S1, S2 and S2 extensive domains of the enzyme, the binding
mode of pyrimidine-2,4-dione derivatives/analogs differs with additional
interactions in S1′ and S2′ pockets. Three general schemes
of fragmented gliptins and gliptin-like structures with the enzyme
and protein–ligand interaction fingerprints were made, which
might be useful in the creation of DPP-4 inhibitor’s design
strategies.