Docking of Glycokinase with Oxo, Sulfo, and Seleno Derivatives of the Carboxamide Activator S41

Abstract

Inactivation of Glucokinase (GK) is associated with diabetes. Therefore, design of drugs targeting the GK activator site is currently integrated in the strategy of the diabetes treatment. The present work investigated the affinity of 30 ligands to GK based on molecular docking using the Gold 5.6 program. Glucokinase’s structure was derived from the Protein Data Bank (PDB Code 3S41), while the ligands were seleno, sulfo and oxo derivatives of the co-crystallized carboxamide activator (PDB code: S41). The results of the ligand-protein docking revealed that GK formed thermodynamically stable complexes with all ligands. The main forces stabilizing the complexes are lipophilic interactions, enhanced by hydrogen bonds. Ligand molecular areas responsible for lipophilic and hydrogen bonding contacts with amino acid residues in the allosteric site of GK were evidenced by molecular electrostatic potentials (MEPs). Interestingly, twelve of the S41 derivatives interacted with GK more strongly than the co-crystallized activator, while maintaining the lipophilic contacts with key amino acid residues like Arg63, which are catalytically crucial for therapeutic properties of GK activators (GKAs). It is noteworthy that divalent Se and S atoms were also involved in chalcogen bonds in the GKA site. Those bonds were nearly linear like hydrogen bonds. Such bond directionality should guide the design of pharmacophoric ligands containing chalcogen atoms.