Molecular docking of Aβ peptide and its Iowa DN mutant using small molecule inhibitors: Possible mechanisms of Aβ-peptide inhibition.

Alzheimer's disease (AD) is the most common form of neurodegenerative diseases, characterized by the deposition of Aβ (amyloid beta) peptide. In this study, we have unravelled the interactions as well as anti amyloidogenic behaviour of 40 small molecule inhibitors with Aβ peptide and Iowa mutant DN-Aβ1 peptide at atomic level and their modes of binding by docking approaches. The binding mode between wild type peptide and drug is distinctly different from the Iowa-mutant-peptide and drug. Here we proposed possible mechanisms of amyloid beta peptide inhibition by small molecule and prevent monomer-monomer interactions via at least three different mechanisms. In the first mechanism, four catechins efficiently interacted with the C-terminal region of peptides through hydrogen bonds and inhibited the peptides. This may lead to blockage of access of second molecule of Aβ-peptide. Secondly, in the case Iowa mutant D23N-Aβ peptide, same catechin form hydrogen bond with the important mutated Asn residue which acts as hydrogen bond donor and acceptor leading to tight binding of inhibitor with the peptide and may prevent monomer-monomer interactions. The third mechanism relies on the ability of drug molecules to mask hydrophobic residues of the peptide, thereby possibly inhibiting hydrophobic interactions between the two beta peptides.