Computational Modeling of Anti-aggregation Effect of Non-steroidal Anti-inflammatory Drugs in Alzheimer’s Amyloidogenesis




Chang, Wenling Eileen

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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.



Amyloid Beta, Naproxen, Anti-aggregation, REMD, CHARMM, NSAID