Multifunctional Roles of Natural Aaptodine in Alzheimer’s Disease: Insights from DFT and MD Studies

The multifunctional properties of aaptodine A in preventing oxidative stress and inhibiting amyloid-beta (Aβ) aggregation, both of which are considered the main causes of Alzheimer's disease (AD), are the focus of this study. Using the M06-2X and M06 density functional theory (DFT) methods, the study examines the scavenging of HO^· and HOO^· radicals, as well as the reactions involving Fe³⁺/Cu²⁺ chelation. Docking and molecular dynamics (MD) simulations further assess the inhibitory effect of aaptodine A on Aβ aggregation. The findings indicate that aaptodine A exhibits a strong ability to scavenge the HO^· radical (rate constant <i>k</i> = 1.69 × 10¹⁰ M^-1 s^-1); however, it is ineffective against the HOO^· radical. Furthermore, aaptodine A demonstrates significant chelating activity with Cu²⁺, particularly showing effective scavenging ability for both Cu²⁺ and Fe³⁺ ions when the complex formation occurs with two ligands. These bioactivities help suppress the formation of reactive free radicals, often associated with metal ions, and mitigate Cu²⁺-induced neurotoxicity linked to Aβ in AD. Additionally, analyses using MM/PBSA and the accelerated weight histogram (AWH) methods reveal that aaptodine A exhibits a strong binding affinity to Aβ42 fibril structures. Its binding affinities are comparable to those of curcumin, a well-known compound recognized for its ability to inhibit the formation of Aβ fibrils and oligomers. The AWH results with tetramer indicate that aaptodine A binds to both toxic oligomeric species and the mature fibril. As a result, aaptodine A exhibits potential antioxidant activity through a secondary mechanism and may serve as a promising candidate for inhibiting toxic Aβ aggregates associated with AD.