Molecular docking assessment of pyridone derivatives as glucokinase activators

Background: Mutations in glucokinase (GK) gene results in maturity onset diabetes of the young 2 (MODY2). It has been observed that GK activators (GKAs) can activate GK structure and promote glucose phosphorylation and bring blood glucose levels to normal condition. The present study is aimed to identify the binding mode of pyridone derivatives (PDs) as GKAs through molecular docking study. Methods: GK structure was retrieved from the Protein Data Bank (PDB), protonated and energy minimized. A database was constructed with 29 PDs and docked into the allosteric site specified with Y61, R63, S69 and Y215 residues using Molecular Operating Environment (MOE) software. Docking conformations were generated using triangle match algorithm and ranked by London dG scoring function. The binding orientations and strength of interactions were evaluated by ligand interaction module of MOE. Results: Molecular docking of 29 PDs in allosteric site of GK gave reliable docking scores, interestingly arene cationic interactions were observed with the compounds PD1, PD12, PD20 and PD21. R63 residue of allosteric site played a predominant role in binding with PDs. Conclusions: PDs can be potentially useful agents in future management strategies of type 2 diabetes mellitus.