A high-resolution α-glucosidase inhibition profiling for targeted identification of natural antidiabetic products from Lycopodiella cernua (L.) Pic. Serm and their inhibitory mechanism study

Abstract

The targeted identification of α-glucosidase inhibitors from the crude ethyl acetate of Lycopodiella cernua (L.) Pic. Serm (L.cernua) was guided by high-resolution inhibition profiling. The α-glucosidase inhibition profiling and HPLC-QTOF-MS showed tannins and serratenes were the corresponding antidiabetic constituents. Two new serratenes named 3β, 21β-dihydroxyserra-14-en-24-oic acid-3β-(4'-methoxy-5'-hydroxybenzoate) (4), 3β, 21α-dihydroxyserra-14-en-24-oic acid-3β-(4'-methoxy-5'-hydroxybenzoate) (7), together with two known compounds (5 and 6) were isolated. Their structures were elucidated by HR-ESI-MS and NMR. Compounds 5–7 inhibited the α-glucosidase activity in a non-competitive manner with Ki values ranging from 1.29 to 12.9 µM. The molecular docking result unveiled that 4–7 bound to the residues at the channel site, which enabled to block the substrate access. In addition, the molecular dynamics (MD) simulation of the most active compound 7 and α-glucosidase indicated the 4′-methoxy-5′-hydroxybenzoate group formed the stable hydrogen bonds and pi-pi T-shaped interactions with Arg312, Gln350 and Phe300 residues, while the rings D and E were stabilized by hydrophobic interaction.