Hydrophobic interactions at subsite S1′ of human dipeptidyl peptidase IV contribute significantly to the inhibitory effect of tripeptides
| Autor: | Yukari Sagae, Keisuke Ito, Hiroaki Iwata, Yasushi Okuno, Katsuyoshi Masuda, Norimasa Kanegawa, Mitsugu Araki |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Stereochemistry Bioinformatics Human dipeptidyl peptidase 4 Biophysics Peptide Tripeptide Material science of foods Drug binding Biochemistry Type II diabetes Dipeptidyl peptidase Article Hydrophobic effect Biochemical characterization of food 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Computer-aided drug design Biophysical chemistry Structure–activity relationship lcsh:Social sciences (General) lcsh:Science (General) Protein-compound binding mode chemistry.chemical_classification Multidisciplinary Dipeptide Chemistry Tripeptide inhibitor Computer simulation Structure activity relationship Amino acid Dipeptide inhibitor 030104 developmental biology Docking (molecular) Molecular docking lcsh:H1-99 Structural biology Peptides Pharmaceutical chemistry 030217 neurology & neurosurgery lcsh:Q1-390 |
| Zdroj: | Heliyon Heliyon, Vol 6, Iss 6, Pp e04227-(2020) |
| ISSN: | 2405-8440 |
| Popis: | Functional inhibitory peptides of human dipeptidyl peptidase 4 (hDPP4) have been highly anticipated as the active ingredient of functional food for type II diabetes; however, the molecular mechanism of hDPP4 inhibition remains unclear. In this study, we focused on dipeptides and tripeptides, which display structure-function correlations that are relatively easy to analyze, and examined their interactions with hDPP4 on an atomic level using a combination of docking studies and an hDPP4 inhibition assay. First, we performed comprehensive binding mode analysis of the dipeptide library and demonstrated that the formation of a tight interaction with the S1 subsite composing part of the substrate pocket is essential for dipeptides to compete with the substrate and strongly inhibit hDPP4. Next, we synthesized tripeptides by adding various amino acids to the C-terminus of Ile-Pro and Val-Pro, which have especially high inhibitory activity among compounds in the dipeptide library, and measured the hDPP4 inhibitory activity of the tripeptides. When hydrophobic amino acids (Ile, Met, Val, Trp) were added, the inhibitory activity increased several-fold. This phenomenon could be explained as follows: the C-terminal amino acid of the tripeptide formed hydrophobic interactions with Tyr547 and Trp629, which compose the S1′ subsite located relatively outside the substrate pocket, thereby stabilizing the hDPP4-peptide binding. The structural information on the interaction between hDPP4 and peptide inhibitors attained in this study is anticipated to be useful in the development of a more potent hDPP4 competitive inhibitor. Biochemistry; Bioinformatics; Biophysics; Structural biology; Computer simulation; Biophysical chemistry; Pharmaceutical chemistry; Material science of foods; Biochemical characterization of food; Computer-aided drug design; Peptides; Drug binding; Structure activity relationship; Human dipeptidyl peptidase 4; Molecular docking; Protein-compound binding mode; Type II diabetes; Dipeptide inhibitor; Tripeptide inhibitor. |
| Databáze: | OpenAIRE |
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