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

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Citation abstract

A novel bis-γ-butyrolactone grifolamine A ( 1 ), the first γ-butyrolactone dimer from nature, together with three known γ-butyrolactones ( 2 - 4 ), was isolated from the byproduct from Grifola frondosa polysaccharides preparation process. The structure and stereochemistry of grifolamine A (1) were elucidated by extensive spectroscopic 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 α-glucosidase in vitro. The underlying inhibitory mechanism was revealed by surface plasmon resonance (SPR), molecular docking, molecular dynamics (MD) simulation and binding free energy calculation. SPR revealed that grifolamine A exhibited a strong affinity to α-glucosidase with an equilibrium dissociation constant (K D ) value of 1.178 × 10 -4 M. Molecular docking manifested that grifolamine A sat at the active pocket of α-glucosidase by van der Waals force, alkyl interaction and carbon hydrogen bonds, and consequently changed the micro-environmental structure of α-glucosidase. MD simulation revealed that grifolamine A had high binding affinity to α-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 α-glucosidase. Our findings provide valuable information for the design and development of novel α-glucosidase inhibitors based on γ-butyrolactone skeleton.