DOI: https://doi.org/10.55373/mjchem.v28i2.67

Keywords: Aspidxanthone A, Aspidistra letreae, thermodynamic, kinetic, molecular docking, molecular dynamics.

Abstract

Aspidistra letreae, a species found only in central Vietnam, contains diverse bioactive compounds. Among them, aspidxanthone A (AL) has shown notable antioxidant activity. In this study, we used a multi-scale computational strategy to explore how AL exerts its antioxidant effects at the molecular level. Thermodynamic and kinetic analyses revealed that AL scavenged hydroperoxyl radicals primarily through the single electron transfer (SET) mechanism in aqueous environments. The O17 hydroxyl group stood out as the most reactive site, supported by its favourable ionization potential and a total rate constant of 1.28 × 10⁷ M^-1.s^-1. In contrast, in lipid-like environments such as pentylethanoate, the hydrogen atom transfer (HAT) mechanism predominated. Molecular docking simulations demonstrated that AL bound strongly to the Keap1 protein (–9.108 kcal/mol), forming stable interactions with key residues like Tyr334 and Ser363. Compared to known natural antioxidants, AL showed superior binding affinity. Molecular dynamics simulations confirmed the stability of the Keap1–AL complex, suggesting that AL may disrupt the Keap1–Nrf2 interaction and thereby strengthen antioxidant defences. ADMET predictions indicated good oral absorption and safety, though mutagenicity and poor CNS penetration remained limitations. To the best of our knowledge, this work represents the first comprehensive computational characterization of AL as a dual-mode antioxidant, combining radical-scavenging reactivity with Keap1 inhibition. Overall, AL emerges as a promising antioxidant lead compound with dual radical-scavenging and Keap1-inhibitory activity, supporting its further development for treating oxidative stress-related diseases.