Comparative Molecular Insights into the Interaction of Dobutamine, Quercetin, and Fisetin with Amyloid Beta Monomer and Protofibril

One important mechanism in the development of Alzheimer's disease (AD) has been shown to be formation of the amyloid β-peptide (Aβ42) aggregate into toxic oligomers, or fibrils. In this work, we have investigated the molecular mechanism of three molecules namely Dobutamine (DBT), Quercetin, and Fisetin in both preventing an early oligomerization and destabilizing preformed Aβ protofibril. However, all these molecules show potential to Aβ monomer stability which has been shown by our molecular docking and molecular dynamics (MD) simulations. The docking analysis reveals that Aβ monomer binds to DBT via amino acids residues Glu22, Asp1, Glu3, and Ser26. Quercetin prefer its binding to Glu11, Glu22, and Ser26, while Fisetin prefers to bind at position Ala12, Try10, Asp1, and Glu3. All these residues are identified as a hotspot site for protein stability and would contribute to the design of novel inhibitors for the treatment of amyloid aggregation in AD. The stabilization of monomeric subunits was observed by the binding of these three inhibitors during MD simulations by reducing the beta-sheet content and increasing the alpha-helices. Binding of these three molecules to the hydrophobic pocket resulted in the loss of two β-sheets of the Aβ protofibril lost their hydrophobic interactions leads to partial opening of the β-sheets. Interestingly loss of a key salt bridge formed between Asp23-Lys28, increases the unstability of the Aβ protofibril. Thus, we believe that understanding these structural and functional insights would be very useful in developing novel inhibitors for AD treatments by preventing the early oligomerization of Aβ peptides and instability of Aβ protofibril.