Mechanistic insights into Aβ₄₂ aggregation inhibition by bacoside A and withanolide A: An in silico and in vitro...

Insoluble Aβ₄₂ peptides form neurotoxic plaques that disrupt synaptic transmission, contribute to Alzheimer's disease (AD) pathology. In vitro aggregation studies of Aβ₄₂ exhibited a sigmoidal growth curve, highlighting distinct nucleation, elongation, and fibril maturation phases. The anti-amyloidogenic potential of bacoside A (BA) and withanolide A (WA) was assessed at different aggregation stages. Docking studies confirmed that both compounds specifically interact with the KLVFFA stretch of Aβ₄₂, a critical region for monomer self-association and fibril formation. A 500 ns molecular dynamics (MD) simulation of interactions of compounds with disordered Aβ₄₂ (2MXU.pdb) revealed stable binding to monomers, with reduced stability during fibril elongation. BA and WA inhibited α-helix conversion during nucleation, preventing key intermediates required for fibril growth, leading to the formation of non-toxic amorphous aggregates. Additionally, a 100 ns MD simulation with native helical Aβ₄₂ (1Z0Q.pdb) provided insights into their preventive action, reinforcing their early-stage aggregation inhibitory potential. These findings suggest that BA and WA act as promising anti-amyloidogenic agents, stabilizing Aβ₄₂ monomers while preventing fibril growth, thereby offering a potential therapeutic strategy for AD.