Abstract
Alzheimer's disease (AD) is characterized by amyloid-beta (Aβ) plaque accumulation and neurodegeneration. This study identified gyrophoric acid, a lichen-derived phenolic metabolite, as a dual-action Aβ42 inhibitor preventing aggregation and disassembling of mature Aβ42 fibrils. Integrated in silico studies revealed that gyrophoric acid was a strong thermodynamic stabilizer of Aβ42 (MM-GBSA: -27.3 kcal/mol) via entropically driven hydrophobic interactions and disruption of aggregation-prone conformations (100 ns MD simulations). Through biochemical analysis of the fluorescent dye thioflavin T (ThT), gyrophoric acid induced rapid Aβ42 fibril disassembly within 5 h, with time-lapse confocal microscopy quantitatively confirming the near-complete dissolution of large aggregates by 24 h. ADMET profiling revealed favorable pharmacokinetics (moderate oral absorption: 48.5-57.3%; low toxicity) and Lipinski's rule compliance. These results establish gyrophoric acid as a promising natural bioactive compound for anti-AD therapeutics with a unique hydrophobic-stabilization mechanism.