Mechanistic and kinetic insights into the radical scavenging capacity and Keap1-Nrf2 inhibition potency of A-type avenanthramides: DFT and molecular docking

Avenanthramides (AVAs), unique polyphenols in oats, have received much attention due to their biologically beneficial properties. Herein, density functional theory (DFT) calculations and molecular docking were performed to elucidate the structure-antioxidant capacity relationship and underlying mechanism of A-type AVAs under physiological conditions. Further, the interaction effects between AVAs and Kelch-like ECH-associated protein 1 (Keap1) for activating the Nrf2-ARE (nuclear factor-E2-related factor 2-antioxidant response element) signaling pathway were explored. The results showed that the representative A-type AVA <b>2 c_d</b> displayed excellent HOO^• scavenging capacity in water at physiological pH with an overall rate constant (<i>k</i>_overall = 2.97 × 10⁷ M^-1 s^-1) higher than that of reference antioxidants Trolox and BHT, while moderate capacity in lipid-like media. Formal hydrogen atom transfer (fHAT) mechanism is more favored in lipid media, whereas in aqueous solution at physiological pH, the hydrogen transfer from dianion species plays a dominant role (99.4%) in the overall reactivity. The results also highlighted the effects of central double bond, hydroxyl, carboxyl and solvents in antiradical processes. Molecular docking and DFT calculations showed that <b>2c</b> and <b>2 c_d</b> can bind strongly to Keap1 through hydrogen bonding and cysteine residues based covalent binding, which disrupts the Keap1-Nrf2 interaction. Collectively, <b>2c</b> and <b>2 c_d</b> are promising candidates as multifunctional antioxidant with radical trapping and Nrf2 activation effects.