A comparative study of the binding modes of recently launched dipeptidyl peptidase IV inhibitors in the active site
| Autor: | Yoshihito Tanaka, Hiroyuki Kishida, Mika Nabeno, Fumihiko Akahoshi, Ikuko Miyaguchi, Takashi Kadowaki, Shinichi Ishii |
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| Rok vydání: | 2013 |
| Předmět: |
Pyrrolidines
Stereochemistry Dipeptidyl Peptidase 4 Biophysics Adamantane Saxagliptin Crystallography X-Ray Biochemistry Dipeptidyl peptidase chemistry.chemical_compound Structure-Activity Relationship Piperidines X-Ray Diffraction Catalytic Domain Catalytic triad Nitriles Protein Interaction Mapping medicine Serine Humans Vildagliptin Teneligliptin Uracil Molecular Biology Dipeptidyl-Peptidase IV Inhibitors biology Sitagliptin Phosphate Active site Cell Biology Dipeptides Triazoles chemistry Covalent bond Multiprotein Complexes Pyrazines biology.protein Pyrazoles Thiazolidines Oligopeptides Alogliptin medicine.drug Protein Binding |
| Zdroj: | Biochemical and biophysical research communications. 434(2) |
| ISSN: | 1090-2104 |
| Popis: | In recent years, various dipeptidyl peptidase IV (DPP-4) inhibitors have been released as therapeutic drugs for type 2 diabetes in many countries. In spite of their diverse chemical structures, no comparative studies of their binding modes in the active site of DPP-4 have been disclosed. We determined the co-crystal structure of vildagliptin with DPP-4 by X-ray crystallography and compared the binding modes of six launched inhibitors in DPP-4. The inhibitors were categorized into three classes on the basis of their binding subsites: (i) vildagliptin and saxagliptin (Class 1) form interactions with the core S 1 and S 2 subsites and a covalent bond with Ser630 in the catalytic triad; (ii) alogliptin and linagliptin (Class 2) form interactions with the S 1 ′ and/or S 2 ′ subsites in addition to the S 1 and S 2 subsites; and (iii) sitagliptin and teneligliptin (Class 3) form interactions with the S 1 , S 2 and S 2 extensive subsites. The present study revealed that the additional interactions with the S 1 ′, S 2 ′ or S 2 extensive subsite may increase DPP-4 inhibition beyond the level afforded by the fundamental interactions with the S 1 and S 2 subsites and are more effective than forming a covalent bond with Ser630. |
| Databáze: | OpenAIRE |
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