Exploring natural phenolic compounds as amyloid-beta fibril inhibitors: computational insights for Alzheimer's disease.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder and remains one of the leading causes of death in older age. While there is no direct cure for AD, very few FDA-approved drugs are available for managing the symptoms by targeting traditional targets. Amyloid-beta (Aß) peptides were identified as a crucial target for AD therapy, in recent times, phenolic compounds have shown the potential to inhibit Amyloid-beta peptide. These phenolic compounds destabilize Aß aggregation, but their inhibition mechanisms are not clearly understood. In this study, we thoroughly explored the molecular binding mechanism of >1000 phenolic compounds with the Aß fibrils via extra precision (XP) and induced fit docking (IFD) methods. Additionally, molecular dynamics (MD) simulations of the top 10 druglike phenolic compounds were performed with a simulation time of 500 nanoseconds (ns). Our results showed that two promising compounds, Rhapontigenin and Okanin, exhibited superior binding free energy and stability compared to the reference apigenin. These compounds effectively disrupted the Asp23-Lys28 salt bridge interactions and hydrogen bond patterns in the Aß fibril. Furthermore, both the identified compounds showed significant van der Waal's interaction with the Aß fibril. Our findings align with the previous studies and provide additional insights into inhibitory mechanisms at the molecular level. Additionally, this study incorporates analysis of non-covalent interactions and DFT studies to further elucidate the mechanisms. Nevertheless, it is crucial to emphasize that these results are based on in silico analyses and necessitate further experimental validation through in vitro and in vivo studies to confirm their efficacy.