Designing of some Novel Methyl 2-((4-(Benzamido)Phenyl)Sulfanyl)-1,2,3,4-tetrahydro-6-Methylpyrimidine-5-carboxylate Derivatives as Potential Glucokinase Activators through Molecular Docking

Abstract

Aims: Glucokinase (GK) is a cytoplasmic enzyme that metabolizes the glucose to glucose- 6-phosphate and supports the adjusting of blood glucose levels within the normal range in humans. In pancreatic β-cells, it plays a leading role by governing the glucose-stimulated secretion of insulin and in liver hepatocyte cells, it controls the metabolism of carbohydrates. GK acts as a promising drug target for the treatment of patients with type 2 diabetes mellitus (T2DM).
 Study Design: In the current study, the goal is to identify new substituted benzamide derivatives and test them via molecular docking as possible anti-diabetic drugs.
 Place and Duration of Study: The present work has been carried out at S.N.J.B’s S.S.D.J. College of Pharmacy, Neminagar, Chandwad, Nashik, Maharashtra, India during the time period of December-2020 to February-2021.
 Methodology: This work involved designing novel methyl 2-((4-(benzamido)phenyl)sulfanyl)-1,2,3,4-tetrahydro-6-methylpyrimidine-5-carboxylate derivatives and their screening by molecular docking studies to determine the binding interactions for the best-fit conformations in the binding site of the GK enzyme. Autodockvina 1.1.2 in PyRx 0.8 was used to perform the docking studies of all the designed novel derivatives and native ligand against the crystal structure of GK. Based on the results of docking studies, the selected molecules will be tested for their antidiabetic activity in the animal models.
 Results: Amongst the designed derivatives, compounds A2, A3, A8, A10, A11, A13, A14, A16, A17, and A18 have shown better binding free energy (between -8.7 to -10.3 kcal/mol) than the native ligand present in the enzyme structure. In present investigation, many molecules had formed strong hydrogen bond with Arg-63 which indicate the potential to activate GK.
 Conclusion: From above results it has been observed that these designed benzamide derivatives have potential to activate the human GK which enables us to proceed for the syntheses of these derivatives.