Binding mechanism and synergetic effects of xanthone derivatives as noncompetitive α-glucosidase inhibitors: a theoretical and experimental study.

Newly emerged xanthone derivatives have attracted considerable interests as a novel class of potent α-glucosidase inhibitors. To provide insights into the inhibitory and binding mechanisms of xanthone-based inhibitors toward α-glucosidase, we carried out experimental and theoretical studies on two typical xanthone derivatives, i.e., 1,3,7-trihydroxyxanthone and 1,3-dihydroxybenzoxanthone. The results indicate that these two xanthone derivatives belong to noncompetitive inhibitors and induce a loss in the α-helix content of the secondary structure of α-glucosidase. Docking simulation revealed the existence of multiple binding modes, in which polyhydroxyl groups and expanded aromatic rings acted as two key pharmacophores to form H-bonding and π-π stacking interactions with α-glucosidase. The fact that 1,3,7-tridroxyxanthone and 1,3-dihydroxybenzoxanthone exhibited significant synergetic inhibition to α-glucosidase strongly suggests that both xanthone derivatives simultaneously bind to the distinct noncompetitive sites of yeast's α-glucosidase. On the basis of the plausible binding clues, synergetic inhibition can be developed to be a promising strategy to achieve enhanced inhibitory activities.