Abstract:
Alzheimer’s disease (AD) represents a growing biomedical, social, and economical
problem. Millions of people have suffered from the disease globally. Studies have
shown that aggregated forms of amyloid β peptide adversely affect neuronal function
and may represent the causative agent in AD. It has been demonstrated that chronic
treatment with ibuprofen and naproxen reduces the risk of AD and improves the
behavioral impairment for patients with AD. This dissertation utilizes high performance
parallel computing, all-atom molecular dynamics simulation, and protein-ligand docking
to understand the mechanism of the anti-aggregation effect of ibuprofen and naproxen in
Alzheimer’s amyloidogenesis. The results reveal different mechanisms of ligand binding
to the monomers and fibrils formed by Aβ peptides implicated in AD. Binding to Aβ
monomers is mostly governed by ligand-amino acid interactions, whereas binding to the
fibril is determined by the fibril surface geometry and interligand interactions. The antiaggregation
effect of ibuprofen and naproxen is explained by direct competition between
these ligands and incoming Aβ peptides for binding to the fibril.
