Binding Mechanism and Synergetic Effects of Xanthone Derivatives as Noncompetitive α-Glucosidase Inhibitors: A Theoretical and Experimental Study

Abstract

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.

Structure activity related, mechanistic, and modeling studies of gallotannins containing a glucitol-core and α-glucosidase

“…Thus, hydrogen bonds are formed via the hydroxyl groups of these GCGs. Notably, a similar phenomenon has been observed in other phenolic compounds such as xanthone derivatives, 23 resveratrol, and oxyresveratrol. 21 Moreover, more favorable hydrophobic interactions are formed between MF and MJ and α -glucosidase residues (Phe157, Phe158, Leu237, His239, His279 Phe300, and Ala278 for MF, and Phe157, Pro309, Leu237, His239, Leu218, His279, and Arg312 for MJ).…”

“…As previous studies have suggested that the helix structure could be stabilized by targeting compounds with polyhydroxyl groups, 21, 23, 49 our CD results suggest that the helix structures were reduced with increasing concentrations of GA, MF, and MJ. Therefore, this implied that binding site 3 is not targeted by these GCGs.…”

“…23 Typically, two concentrations around the IC 50 values of each sample were chosen (ranging from 2 – 250 μ M). For each concentration, α -glucosidase activities were tested by using different concentrations of pPNP glycoside (1 to 1000 μ M).…”

In Vitro and In Vivo Effects of Norathyriol and Mangiferin on α-Glucosidase

“…However, the nonsugar inhibitors of α -glucosidase have drawn the attention of researcher because of the limitations of sugar-mimicking inhibitors. Norathyriol and mangiferin have the same basic structure, the xanthone backbone, which is the molecular basis for α -glucosidase inhibition [11]. In the enzyme assays, norathyriol and mangiferin showed more potent inhibition of α -glucosidase than positive control (acarbose).…”

Effects of Synergistic Inhibition on α-glucosidase by Phytoalexins in Soybeans

“…Therefore, complicated synergistic mechanisms are likely to be involved in many biological events in other investigations of mechanisms of α-glucosidase inhibition [30]. Liu et al demonstrated that a combination of inhibitors improves α-glucosidase inhibition [31]. They selected two typical xanthone derivatives (1,3,7-trihydroxyxanthone and 1,3-dihydroxybenzoxanthone) and observed their synergistic effect.…”