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Nonsteroidal anti-inflammatory drug naproxen destabilizes A? amyloid fibrils: a molecular dynamics investigation.


ABSTRACT: Using implicit solvent model and replica exchange molecular dynamics, we examine the propensity of a nonsteroidal anti-inflammatory drug, naproxen, to interfere with A? fibril growth. We also compare the antiaggregation propensity of naproxen with that of ibuprofen. Naproxen's antiaggregation effect is influenced by two factors. Similar to ibuprofen, naproxen destabilizes binding of incoming A? peptides to the fibril due to direct competition between the ligands and the peptides for the same binding location on the fibril surface (the edge). However, in contrast to ibuprofen, naproxen binding also alters the conformational ensemble of A? monomers by promoting ?-structure. The second factor weakens naproxen's antiaggregation effect. These findings appear to explain the experimental observations, in which naproxen binds to the A? fibril with higher affinity than ibuprofen, yet produces weaker antiaggregation action.

SUBMITTER: Takeda T 

PROVIDER: S-EPMC3034367 | biostudies-literature | 2010 Nov

REPOSITORIES: biostudies-literature

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Nonsteroidal anti-inflammatory drug naproxen destabilizes Aβ amyloid fibrils: a molecular dynamics investigation.

Takeda Takako T   Kumar Rashmi R   Raman E Prabhu EP   Klimov Dmitri K DK  

The journal of physical chemistry. B 20101027 46


Using implicit solvent model and replica exchange molecular dynamics, we examine the propensity of a nonsteroidal anti-inflammatory drug, naproxen, to interfere with Aβ fibril growth. We also compare the antiaggregation propensity of naproxen with that of ibuprofen. Naproxen's antiaggregation effect is influenced by two factors. Similar to ibuprofen, naproxen destabilizes binding of incoming Aβ peptides to the fibril due to direct competition between the ligands and the peptides for the same bin  ...[more]

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