Inhibitory mechanism of α-glucosidase by liquiritigenin and its combined effect with acarbose: Multi-spectroscopic analyses and molecular docking simulation

Identification of new α -glucosidase ( α -Glu) inhibitors from natural sources is very important to the management of type 2 diabetes. In this work, liquiritigenin (LTG), a flavonoid compound derived from liquorice, was found to have excellent inhibition of α -Glu (IC 50  = 27.91 ± 3.48 μM) in a mixed manner. LTG reduced the endogenous fluorescence of α -Glu in a static mode by spontaneously forming stable complexes with the α -Glu-substrate through hydrophobic forces and hydrogen bonding. LTG decreased the α -helix and β -sheet contents of α -Glu while increasing the β -turn and random coil contents. Computer simulation showed that LTG interacted non-covalently with Gly161, Glu422, Glu429, and Asn235 residues of α -Glu, causing structural unfolding of the enzyme, which affected the substrate-enzyme interaction and ultimately reduced the release of the product. While acarbose, a competitive inhibitor of α -Glu, spontaneously hydrogen-bonded Tyr158, His280, Asp242, and Asp352 residues of the LTG− α -Glu complex. Moreover, a combination of LTG (6.00 μM) and acarbose (30.00 μM) had a remarkable synergistic inhibition on α -Glu, which may be because LTG made the structure of α -Glu loosening and reduced its catalytic activity through allosteric effect. And the occupation of the active cavity by acarbose may lead to a conformational change in the LTG− α -Glu complex, which effectively hindered the binding between the substrate and α -Glu. These findings may offer a new theoretical foundation for the development of LTG as a glucose-lowering ingredient in functional foods.