Identification of small-molecule glucokinase activator for type-2-diabetes treatment: a structure-based virtual screening approach

Abstract

ABSTRACT Glucokinase (GK, EC 2.7.1.2) is a crucial enzyme that catalyses the conversion of glucose to glucose-6-phosphate. It is used to treat type-2 diabetes (T2D), a serious metabolic disorder that is still at the forefront without proper medication. Fast Rigid Exhaustive Docking (FRED) was carried out for 400,000 compounds from the Zinc database to identify novel glucokinase activators. The hit compounds ZINC69775727, ZINC9114647, ZINC91773667, ZINC9305321, and ZINC96165848 interacted strongly with allosteric site residues and, formed hydrogen bonds with ARG 63. The hit compounds met the criterion for drug-likeness, according to the ADME prediction. The compounds were then subjected to 100 ns of molecular dynamics simulation and MM-GBSA calculation using DESMOND. The findings demonstrated that the compounds had good stability and minimal fluctuation throughout the course of the simulation, pointing to the potential of the chosen compounds for glucokinase activation. The compound ZINC69775727 in particular has the lowest binding energy of −111.1 kcal/mol, which is lower than the native ligand’s binding energy of −102.84 kcal/mol and the binding energies of the control compounds PSN-GK1 and Piragliatin, which are −102.49 kcal/mol and −107.767 kcal/mol, respectively. Therefore, the information from this work may be useful in finding novel small molecules as GKAs.