Hesperetin-Cu(II) complex as potential α-amylase and α-glucosidase inhibitor: Inhibition mechanism and molecular docking

Inhibition of α-amylase and α-glucosidase activity is an effective way for controlling postprandial blood glucose-related diabetes. The study found that hesperetin-Cu(II) complex (Hsp-Cu(II)) exhibited a stronger inhibitory ability on α-amylase and α-glucosidase compared to hesperetin (Hsp), with smaller IC50 values of Hsp-Cu(II) (60.3 ± 0.9 µM for α-amylase; 1.25 ± 0.03 µM for α-glucosidase) than Hsp (115.6 ± 1.1 µM for α-amylase; 55.2 ± 0.1 µM for α-glucosidase). Interestingly, Hsp-Cu(II) and acarbose exerted a synergistic effect on inhibition of α-glucosidase. The binding affinities of Hsp-Cu(II) to α-amylase and α-glucosidase were strong with the Ka values (binding constant) in the magnitude order of 105, which was 9 times larger than Hsp. After interacting, Hsp-Cu(II) reduced α-helix contents of α-amylase and α-glucosidase, resulting in a looser conformation of these two enzymes. Molecular simulations manifested that Hsp-Cu(II) bound to the active center of enzymes driven by hydrogen bonds and interacted with the key catalytic amino acids (α-amylase: Gln63, Asp300 and His305; α-glucosidase: Tyr158, Asp215, Glu277 and Glu411), altering the conformation of enzymes, blocking the entrance of substrates, ultimately reducing the activities of α-glucosidase and α-amylase. This study has demonstrated that Hsp-Cu(II) may be a promising candidate of functional nutritional additive and medicine for the prevention of diabetes.