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 alpha-aminoacyl linker, (ii) structures with trifluorophenyl moiety or analogs as P1 fragment with beta-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.

Automated summary

This study classifies approved and potent DPP-4 inhibitors with gliptin-like structures into three groups based on their structures and mechanisms of inhibition, showing different binding modes in various domains of the enzyme. The analysis of structure-activity relationship and protein-ligand interaction fingerprints provides insights for the design strategies of DPP-4 inhibitors.