Sesquiterpenoids from Lindera aggregata with Keap1 binding affinity: Chemical diversity and bioactivity screening

Phytochemical investigation of Lindera aggregata roots led to the isolation and identification of 20 sesquiterpenoids (1–20), including a new germacrane-type derivative (1) and five congeners (6, 10–11, and 14–15) reported for the first time in this genus. Structural elucidation, based on NMR, HRESIMS, and ECD analysis, classified these compounds into five distinct chemical subtypes: germacrane (1–6), eudesmane (7–16), guaiane (18–19), lindenane (17), and elemane (20). To assess their potential bioactivity, an affinity ultrafiltration screening (AUS) assay, coupled with ultra-performance liquid chromatography-mass spectrometry (UPLC-MS) analysis, was performed using Kelch-like ECH-associated protein 1 (Keap1) as the target protein. The results indicated that 14 compounds exhibited significant binding affinity to Keap1. Molecular docking studies further revealed that compounds 2, 4, and 8 displayed the strongest interactions, with binding energies of −9.6, −9.2, and −8.6 kcal/mol, respectively. These compounds primarily interact with Keap1 through hydrogen bonding with residues ASN-414, ARG-415, VAL-465, and ILE-559, and hydrophobic interactions with residues ALA-366, GLY-367, GLY-464, GLY-558, and Ile-559. These findings suggested that these sesquiterpenoids may exert antioxidant and neuroprotective effects by modulating the Keap1-Nrf2 signaling pathway, providing new insights into the pharmacological potential of L. aggregata.