Ajmer Singh Grewal1, 2*, Rajeev Kharb3, Jagdeep Singh Dua4, Viney Lather3
1Chitkara College of Pharmacy, Chitkara University, Rajpura, 140401, Punjab, India
2I. K. Gujral Punjab Technical University, Jalandhar, 144601, Punjab, India
3Amity Institute of Pharmacy, Amity University, Noida, 201303, U.P., India
4Shivalik College of Pharmacy, Naya-Nangal, 140126, Punjab, India
*Address for Correspondence
Ajmer Singh Grewal,
Chitkara College of Pharmacy, Chitkara University, Rajpura, 140401, Punjab, India
Abstract
Objective: Glucokinase (GK) activators are newer emerging class of therapeutic candidates, which activate GK in pancreatic β-cells and liver hepatocytes and show their hypoglycemic activity. The maximum drug discovery and development programmes linked to GK activators were primarily centered on the N-heteroaryl substituted benzamide derivatives. The present work was planned to predict the binding mode of a series of N-heteroaryl benzamide derivatives in the allosteric site of GK enzyme in a way to design newer GK activators. Material and Methods: A series of N-heteroaryl benzamide derivatives with reported high GK activity from literature were selected for the molecular docking studies. In silico molecular docking studies were performed for the selected derivatives in the allosteric binding site of GK protein using AutoDock Vina. Results: The superimpose of the docked poses of the selected benzamide derivatives with the GK-reference activator complex showed that the selected derivatives have the analogous binding pattern with the allosteric site residues of the enzyme as that of reference ligand. The results of the docking studies indicated that the amide group of the benzamide is required for the H-bonding interactions with Arg63 residue of GK protein and the aromatic rings are essential for the hydrophobic interactions with the residues in hydrophobic pocket in allosteric site of the GK protein. Conclusion: This information can be utilized to design novel potent, safe and effective GK activators based on benzamide scaffold for type 2 diabetes therapeutics.
Keywords: AutoDock, Benzamides, Docking, Glucokinase, GK activators, Type 2 diabetes
