Mechanistic insights into the radical scavenging activity and Keap1 Nrf2 inhibition potential of selected avenanthramides using DFT and molecular dynamics studies

Avenanthramides (AVs) are phenolic alkaloids found exclusively in oats (Avena sativa) and are known for their antioxidant properties. In this study, the antioxidant potential of eight AVs ( 2p , 2f , 2c , 2s , 1p , 1f , 1c , and 1s ) was investigated using DFT-based quantum-chemical studies and protein–ligand interaction analyses. Antioxidant activity was evaluated using thermodynamic and kinetic analyses of hydroperoxyl radical (OOH) scavenging. The results revealed that the hydrogen atom transfer mechanism predominates, with caffeic acid-derived ( 1c and 2c ) and sinapic acid-derived ( 1s and 2s ) AVs exhibiting the highest radical-scavenging efficiencies. The potential of these compounds to modulate the Keap1–Nrf2 antioxidant defense pathway was assessed through molecular docking, molecular dynamics simulations, and MM-PBSA binding free-energy calculations. All AVs showed favorable binding within the Keap1 binding pocket, while 2f , 1s , and 2s exhibited particularly favorable binding free energies and stable protein–ligand complexes. Pharmacokinetic and drug-likeness analyses further supported their therapeutic potential. Taken together, the findings identify 1c and 2c as potent radical scavengers and highlight 2f , 1s , and 2s as promising Keap1-targeting candidates for the management of oxidative stress.