Grifolamine A, a novel bis-gamma-butyrolactone from Grifola frondosa exerted inhibitory effect on alpha-glucosidase and their binding interaction: Affinity and molecular dynamics simulation

A novel bis-gamma-butyrolactone grifolamine A (1), the first gamma-butyrolactone dimer from nature, together with three known gamma-butyrolactones (2-4), was isolated from the byproduct from Grifola frondosa polysaccharides prepa-ration process. The structure and stereochemistry of grifolamine A (1) were elucidated by extensive spectro-scopic analysis combined with quantum chemical calculation. The biosynthetic origin of compound 1, as well as 2-4 was proposed. Grifolamine A (1) showed an intense inhibition against alpha-glucosidase in vitro. The underlying inhibitory mechanism was revealed by surface plasmon resonance (SPR), molecular docking, molecular dy-namics (MD) simulation and binding free energy calculation. SPR revealed that grifolamine A exhibited a strong affinity to alpha-glucosidase with an equilibrium dissociation constant (KD) value of 1.178 x 10-4 M. Molecular docking manifested that grifolamine A sat at the active pocket of alpha-glucosidase by van der Waals force, alkyl interaction and carbon hydrogen bonds, and consequently changed the micro-environmental structure of alpha-glucosidase. MD simulation revealed that grifolamine A had high binding affinity to alpha-glucosidase with average free energy of-25.2 +/- 3.2 kcal/mol. Free energy decomposition indicated amino acid residues including PHE298, PHE308, PHE309, PHE155 and ARG310 at the binding pocket played a strongly positive effect on the interaction between grifolamine A and alpha-glucosidase. Our findings provide valuable information for the design and development of novel alpha-glucosidase inhibitors based on gamma-butyrolactone skeleton.