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

Harika Meduru,Yeng-Tseng Wang,Jeffrey Tsai,Yu-Ching Chen

doi:10.3390/ijms17060920

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.

Highlights

Worldwide 314 million individuals are suffering from type-2 diabetes mellitus, which has been classified as a disease of glucose overproduction by tissues lacking enough insulin production [1]
The infirmity of insulin secretion and insulin action on glucose uptake in muscles leads to type-2 diabetes mellitus [3]
We have explored structurally diverse compounds from the literature and performed molecular docking (CDOCKER) which revealed the importance of Dipeptidyl peptidase-4 (DPP-4) central β-amino butyl amide moiety for binding modes

Summary

Introduction

Worldwide 314 million individuals are suffering from (metabolic disorder) type-2 diabetes mellitus, which has been classified as a disease of glucose overproduction by tissues lacking enough insulin production [1]. Insulin resistance is one of the major associated conditions for most patients with the disorder, and is generally present in people suffering with obesity [2]. The infirmity of insulin secretion and insulin action on glucose uptake in muscles leads to type-2 diabetes mellitus [3]. The function of glucagon like peptide-1 (GLP-1) and its potential role in treating type-2 diabetes was first reported in late 1990s [5]. Glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP) are intestinally derived incretin hormones, which physiologically arouse insulin emissions from β-cells postprandially (Figure 1) [6]. GLP-1 has multiple advantageous effects on beta-cell chore and mass by stimulating beta-cell development from precursor cells and inhibiting

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