Discovery of Natural α-Glucosidase Inhibitors from Hericium erinaceus Through Integrated Isolation, Structural Characterization, In Vitro Evaluation, and Molecular Dynamics Simulations

Recognized for its dual nutritional and therapeutic value, the fungus Hericium erinaceus is increasingly acknowledged as a rich resource of naturally derived α-glucosidase inhibitors. In this study, eight compounds were isolated from H. erinaceus, including three novel compounds designated as erinacerins X−Z (1, 2, and 6). Their absolute configurations were definitively elucidated using a combination of NMR, HR-MS, and ECD calculations. Furthermore, an integrated screening strategy combining molecular docking, molecular dynamics (MD) simulations, and surface plasmon resonance (SPR) analysis identified two isoindolin-1-ones (2 and 3) as potent naturally derived α-glucosidase inhibitors. Notably, in vitro testing established compounds 2 and 3 as robust α-glucosidase inhibitors, affording IC50 values of 17.80 ± 1.03 μM and 19.50 ± 1.33 μM, respectively. MD simulations revealed that electrostatic interactions and van der Waals forces are the primary drivers of this intermolecular association. These findings were further corroborated by SPR analysis, which quantified their high-affinity binding kinetics to the enzyme. Overall, this combined approach establishes a solid foundation for the discovery and development of natural α-glucosidase inhibitors from H. erinaceus.