Clinical Pharmacology & Biopharmaceutics
Open Access

Abstract

Glucokinase (GK) enzyme is involved in glucose utilization in liver and has also been implemented in Glucose-dependant release of insulin in the pancreatic �?²-cell. Activation of glucokinase enzyme therefore, has emerged as a strategy to increase glucose utilization. The world-wide endeavours to design compounds (GKA: Glucokinase activators) that would activate the glucokinase enzyme so as to develop suitable drugs to treat Type 2 diabetes, has culminated in library of numerous compounds; benzamide derivatives have been at mainstay amongst them. The ligand-protein interaction involves ARG63 as the anchoring residue, and many more residues as TYR210, TYR215, etc. which are submerged in a cleft between two domains. Albeit, binding of the ligands with amidine backbone of ARG63 and the hydrogen-bond interactions of the free amino group on ligands with TYR215 is believed to be involved in activation of the enzyme, the free amino group had been noticed to elicit mutagenic effects. Present work describes the design, docking of benzamide derivatives that bind with ARG63, much the way similar to the standard GKA, RO-28-1675, and interact with other set of amino acid residues in much similar way, however, without the presence of free amino group. Molecular modeling studies involved, Molecular Design Suite (VLife MDS 3.5), simulated protein 1V4S, virtual structures of standard and newly designed benzamide derivatives. The structures were docked in the catalytic site of 1V4S to obtain respective docking score (in KJ/mol) and the amino acid residue involved in each interaction. Based on the study, few molecules were selected for synthesis and other molecules were outright rejected. The criteria for such selection, scheme of reactions to synthesize selected molecules, results of their in vitro binding with glucokinase enzyme are presented. The obtained results do not promise to yield better GKA than the standard compound. However, the molecules could further be subjected to rational changes in structure and re-subject to in silico studies so as to yield molecules to activate GK.

Biography

Email: vchatpalliwar@yahoo.co.in