Abstract
Experimental and epidemiological studies have shown that the nonsteroidal antiinflammatory drug naproxen may be useful in the treatment of Alzheimer's disease. To investigate the interactions of naproxen with A β dimers, which are the smallest cytotoxic aggregated A β peptide species, we use united atom implicit solvent model and exhaustive replica exchange molecular dynamics. We show that naproxen ligands bind to A β dimer and penetrate its volume interfering with the interpeptide interactions. As a result naproxen induces a destabilizing effect on A β dimer. By comparing the free-energy landscapes of naproxen interactions with A β dimers and fibrils, we conclude that this ligand has stronger antiaggregation potential against A β fibrils rather than against dimers. The analysis of naproxen binding energetics shows that the location of ligand binding sites in A β dimer is dictated by the A β amino acid sequence. Comparison of the in silico findings with experimental observations reveals potential limitations of naproxen as an effective therapeutic agent in the treatment of Alzheimer's disease.
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