Comparative study of antidiabetic potential of major phytochemicals in bitter melon (Momordica charantia): Computational insights

Abstract

Diabetes mellitus is one of the most common diseases that can be found in both developed and developing countries. The fruit of bitter melon, Momordica charantia is popular among Asians because of its significant antidiabetic potential. The human GSK-3 protein is known to phosphorylate and inactivate glycogen synthase, which is utilized as a negative regulator in the hormone-regulated maintenance of glucose homeostasis. The antidiabetic substances (Charantin, Vicine, Momordenol, and Momordicilin) which derived from bitter melon activate glycogen synthase by blocking the active site of the GSK-3 protein. These ligands enhance insulin sensitivity and promote glucose uptake into the cell. This research was aimed to investigate and compare the binding affinities of these antidiabetic phytochemicals with the GSK-3 protein. The molecular structures of the ligands were retrieved from the PubChem database. Ligands were optimized geometrically using the density functional theory with B3LYP functional and 6-311G++ (d, p) basis set, employing software of Gaussian-09. The 3D structures of GSK-3 protein molecules were downloaded from the Protein Data Bank (PDB ID: 1Q5K). It contains both isoforms, GSK-3α and GSK-3β. The Lamarckian genetic algorithm was used for docking studies using AutoDock 4.2. Molecular interactions between protein-ligand (antidiabetic substances) complexes, bond lengths, and amino acids in binding pockets were analyzed by using the Discovery Studio. Among these four anti-diabetic substances used for this computational study, Momordenol, with the highest binding affinity (-9.91 kcal/mol) for GSK-3 protein, forms a strong and stable complex with the protein. This strong binding enhances its inhibition efficacy by preventing GSK-3 from functioning effectively, leading to greater inhibition potential. In this study, we also compared the binding energies and inhibition constants of N-(4-Methoxybenzyl)-N'-(5-Nitro-1,3- Thiazol-2-Yl) Urea (AR-A014418), a known GSK-3 inhibitor (-7.59 kcal/mol, 2.74 µM), with Momordenol (-9.91 kcal/mol, 0.05411 µM), Momordicilin (-9.51 kcal/mol, 0.10359 µM), Charantin (- 8.49 kcal/mol, 0.59355 µM), and Vicine (-6.71 kcal/mol, 11.99 µM). The results show that Momordenol has the strongest binding affinity and the lowest inhibition constant, indicating superior inhibitory potential. By using AR-A014418 as a reference, this comparison highlights Momordenol as a promising therapeutic candidate for targeting GSK-3 protein, offering potential advantages in drug development. The comparative study exhibited the anti-diabetic potential of these four major phytochemicals present in the fruit of bitter melon follow the order of Momordenol > Momordicilin > Charantin > Vicine. These computational insights encourage the design of structurally novel antidiabetic substances which will be more economical and beneficial in the pharmaceutical industry.