The in Silico Study of Nutmeg Seeds (Myristica fragrans Houtt) as Peroxisome Proliferator Activated Receptor Gamma Activator Using 3D-QSAR Pharmacophore Modelling

M Muchtaridi,Keri Lestari,Karen Low

doi:10.7324/japs.2016.60907

Abstract

In this study, we created pharmacophore models from a dataset of agonists for PPAR gamma receptor using the Catalyst/Hypogen module. A training set consists of 22 compounds activity range between 0.1 to 3,500 nM, were carefully selected. In previous study, molecular docking of macelignan against PPARγ binding pocket showed a free energy binding of -11.07 kJ/mol, interaction with the hydrophobic pocket (diphenyl pocket) (Celik et al., 2007), and a hydrogen bond network (His323, Tyr473, His449 and Ser289) . The pharmacophore model (Hypo1), consisting of 5 features, i.e. one hydrogen bond acceptor (HBA), negative ionizable (NI), ring aromatic (RA) and two hydrophobics (HY) features, and one excluded volume. Hypo1 has the lowest total cost value (92.055), the highest cost difference (40,9316), the lowest RMSD (0.591049), and the best correlation coefficient (0.972949). Fourteen natural reported from nutmeg seeds (Myristica fragrans HOUTT.) were then mapped against Hypo1, and macelignan shows a fair fit value of 7.00102 with an estimated value of 1271.990 nM. This concludes, macelignant in nutmeg might have antidiabetic properties via PPARγ receptor activation.

Highlights

Peroxisome Proliferator-Activated Receptors (PPARs) are members of the nuclear receptor super-family that is involved in protein gene expression for energy, glucose and lipid metabolism, proliferation and differentiation of adipocyte, as well as insulin sensitivity (Arck et al, 2010; Hiukka et al, 2010; Farce et al, 2009)
PPARγ agonist has made a big attraction in the clinical management of cardiovascular risk factors associated with metabolic syndrome and Type 2 diabetes mellitus (Pearson, 2009)
Selecting Training Set Compound Choosing the training set is important for generating a hypothesis in the Hypogen and has to follow certain ground rules, such as a minimum of 16 varieties of structural compound has to be chosen to avoid by chance of correlation

Summary

Introduction

Peroxisome Proliferator-Activated Receptors (PPARs) are members of the nuclear receptor super-family that is involved in protein gene expression for energy, glucose and lipid metabolism, proliferation and differentiation of adipocyte, as well as insulin sensitivity (Arck et al, 2010; Hiukka et al, 2010; Farce et al, 2009). Three isoforms of these core receptors have been identified so far: PPARα, PPARβ/δ dan PPARγ. PPARγ agonist has made a big attraction in the clinical management of cardiovascular risk factors associated with metabolic syndrome and Type 2 diabetes mellitus (Pearson, 2009)

Objectives

Methods

Results