Structure-Activity Relationship Analysis of Cocrystallized Gliptin-like Pyrrolidine, Trifluorophenyl, and Pyrimidine-2,4-Dione Dipeptidyl Peptidase-4 Inhibitors
| Autor: | Budimir S. Ilić, Katarina Tomovic, Andrija Smelcerovic |
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| Rok vydání: | 2021 |
| Předmět: |
Models
Molecular Pyrrolidines Pyrimidine Stereochemistry Dipeptidyl Peptidase 4 Relationship analysis Crystallography X-Ray 01 natural sciences Pyrrolidine 03 medical and health sciences chemistry.chemical_compound Structure-Activity Relationship Drug Discovery Moiety Structure–activity relationship Humans Dipeptidyl peptidase-4 030304 developmental biology chemistry.chemical_classification 0303 health sciences Dipeptidyl-Peptidase IV Inhibitors Dose-Response Relationship Drug Molecular Structure Chemistry 0104 chemical sciences 010404 medicinal & biomolecular chemistry Enzyme Molecular Medicine Linker |
| Zdroj: | Journal of medicinal chemistry. 64(14) |
| ISSN: | 1520-4804 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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