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Int J Mol Sci. 2016 Jun 13;17(6). pii: E920. doi: 10.3390/ijms17060920.

Finding a Potential Dipeptidyl Peptidase-4 (DPP-4) Inhibitor for Type-2 Diabetes Treatment Based on Molecular Docking, Pharmacophore Generation, and Molecular Dynamics Simulation.

Author information

1
Department of Bioinformatics and Medical Engineering, Asia University, 500, Lioufeng Rd., Wufeng, Taichung 41354, Taiwan. harikameduri.bioinfo@gmail.com.
2
Department of Biochemistry, Kaohsiung Medical University, 100, Shih-Chuan 1st Road, Kaohsiung 80708, Taiwan. c00jsw00@kmu.edu.tw.
3
Department of Bioinformatics and Medical Engineering, Asia University, 500, Lioufeng Rd., Wufeng, Taichung 41354, Taiwan. president@asia.edu.tw.
4
Department of Bioinformatics and Medical Engineering, Asia University, 500, Lioufeng Rd., Wufeng, Taichung 41354, Taiwan. yuching33@gmail.com.

Abstract

Dipeptidyl peptidase-4 (DPP-4) is the vital enzyme that is responsible for inactivating intestinal peptides glucagon like peptide-1 (GLP-1) and Gastric inhibitory polypeptide (GIP), which stimulates a decline in blood glucose levels. The aim of this study was to explore the inhibition activity of small molecule inhibitors to DPP-4 following a computational strategy based on docking studies and molecular dynamics simulations. The thorough docking protocol we applied allowed us to derive good correlation parameters between the predicted binding affinities (pKi) of the DPP-4 inhibitors and the experimental activity values (pIC50). Based on molecular docking receptor-ligand interactions, pharmacophore generation was carried out in order to identify the binding modes of structurally diverse compounds in the receptor active site. Consideration of the permanence and flexibility of DPP-4 inhibitor complexes by means of molecular dynamics (MD) simulation specified that the inhibitors maintained the binding mode observed in the docking study. The present study helps generate new information for further structural optimization and can influence the development of new DPP-4 inhibitors discoveries in the treatment of type-2 diabetes.

KEYWORDS:

CDOCKER; DPP-4 inhibitors; GIP; GLP-1; incretin; molecular dynamics simulation; pharmacophore generation; type-2 diabetes

PMID:
27304951
PMCID:
PMC4926453
DOI:
10.3390/ijms17060920
[Indexed for MEDLINE]
Free PMC Article

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