Molecular Docking of Aβ1–40 Peptide and Its Iowa D23N Mutant Using Small Molecule Inhibitors: Possible Mechanisms of Aβ-peptide Inhibition

Document Type

Article

Publication Date

2019

Keywords

Alzheimer's disease, Iowa mutant, Polyphenols

Digital Object Identifier (DOI)

https://doi.org/10.1016/j.ijbiomac.2018.12.271

Abstract

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 Aβ1–40 peptide and Iowa mutant D23N-Aβ115–42 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-Aβ15–42 peptide, same catechin form hydrogen bond with the important mutated Asn23 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.

Was this content written or created while at USF?

Yes

Citation / Publisher Attribution

International Journal of Biological Macromolecules, v. 127, p. 250-270

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