Inhibition of α-glucosidase by 2-thiobarbituric acid: Molecular dynamics simulation integrating parabolic noncompetitive inhibition kinetics

Abstract

Abstract The phenomenon of α-glucosidase inhibition has attracted the attention of researchers due to its association with type 2 diabetes treatment in humans. In this study, we found that 2-thiobarbituric acid (TBA) induces complex inhibition of α-glucosidase using kinetics tests and molecular dynamics (MD) simulations. Computational MD and docking simulations demonstrate that TBA interacts with three residues on active sites of α-glucosidase such as Met69, Arg212, and His348. These biochemical tests indicate that TBA reversibly inhibits α-glucosidase in a parabolic noncompetitive manner ( IC 50 = 17.13 ± 1.14 mM; K i = 13.25 ± 0.56 mM) and that this inhibition is accompanied by a biphasic kinetic process. The tertiary conformational changes were not synchronized with TBA inhibition but we observed hydrophobic disruption after inactivation at higher concentrations of TBA. Our results provide insight into the functional roles of residues located at the active sites of α-glucosidase, and we suggest that compounds similar to TBA (heterocyclic compounds) targeting the key residues of active sites are potential α-glucosidase inhibitors.