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Int. J. Mol. Sci. 2016, 17(6), 920; 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

1
Department of Bioinformatics and Medical Engineering, Asia University, 500, Lioufeng Rd., Wufeng, Taichung 41354, Taiwan
2
Department of Biochemistry, Kaohsiung Medical University, 100, Shih-Chuan 1st Road, Kaohsiung 80708, Taiwan
*
Author to whom correspondence should be addressed.
Academic Editor: Jesus De Julián Ortiz
Received: 15 April 2016 / Revised: 30 May 2016 / Accepted: 2 June 2016 / Published: 13 June 2016
(This article belongs to the Section Physical Chemistry, Theoretical and Computational Chemistry)
View Full-Text   |   Download PDF [2743 KB, uploaded 13 June 2016]   |  

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. View Full-Text
Keywords: incretin; GLP-1; GIP; DPP-4 inhibitors; type-2 diabetes; CDOCKER; pharmacophore generation; molecular dynamics simulation incretin; GLP-1; GIP; DPP-4 inhibitors; type-2 diabetes; CDOCKER; pharmacophore generation; molecular dynamics simulation
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).

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MDPI and ACS Style

Meduru, H.; Wang, Y.-T.; Tsai, J.J.P.; Chen, Y.-C. Finding a Potential Dipeptidyl Peptidase-4 (DPP-4) Inhibitor for Type-2 Diabetes Treatment Based on Molecular Docking, Pharmacophore Generation, and Molecular Dynamics Simulation. Int. J. Mol. Sci. 2016, 17, 920.

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