Meroterpenoids as PTP1B and α-glucosidase inhibitors from the fruiting bodies of Ganoderma guinanense

Ganoderma fungi have long been used as functional foods and traditional medicines in Asian countries. Five previously undescribed and five known meroterpenoids were isolated from the fruiting bodies of Ganoderma guinanense. The structures of undescribed compounds, named ganoduriporols M-Q (1-5), were elucidated by spectroscopic data including NMR and HRESIMS. Compounds 1, 2, and 4-10 exhibited notable α-glucosidase inhibitory activity (IC₅₀, 1.67-21.16 μM), markedly superior to acarbose, among which 1 and 5 were the most potent, showing 60-fold and 126-fold greater inhibition, respectively. This series of compounds also inhibited PTP1B (IC₅₀, 2.83-53.42 μM), with the most potent being 1, 2, 9, and 10, showing greater activity than the positive control. Enzyme kinetics identified nine active meroterpenoids as non-competitive/mixed-type α-glucosidase and PTP1B inhibitors. Molecular docking revealed that hydrogen-bond interactions between the meroterpenoids and key residues of α-glucosidase and PTP1B contributed to enhanced binding specificity, while salt bridges and π-stacking interactions stabilized these compounds within the enzyme active sites. This study investigates Ganoderma meroterpenoids for diabetes treatment and identifies natural-derived antidiabetic candidates.