Nonsteroidal anti-inflammatory drug naproxen destabilizes Aβ amyloid fibrils: a molecular dynamics investigation.
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 binding location on the fibril surface (the edge). However, in contrast to ibuprofen, naproxen binding also alters the conformational ensemble of Aβ monomers by promoting β-structure. The second factor weakens naproxen's antiaggregation effect. These findings appear to explain the experimental observations, in which naproxen binds to the Aβ fibril with higher affinity than ibuprofen, yet produces weaker antiaggregation action.
Takeda
Takako
T
Department of Bioinformatics and Computational Biology, George Mason University, Manassas, Virginia 20110, USA.
Kumar
Rashmi
R
Raman
E Prabhu
EP
Klimov
Dmitri K
DK
D000595:Amino Acid Sequence; D000682:Amyloid / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000737:chemistry*; D007052:Ibuprofen / Q000737:chemistry; D008958:Models, Molecular; D056004:Molecular Dynamics Simulation; D008969:Molecular Sequence Data; D009288:Naproxen / Q000737:chemistry*; D011487:Protein Conformation; D012997:Solvents / Q000737:chemistry
D000682:Amyloid; D016229:Amyloid beta-Peptides; D000894:Anti-Inflammatory Agents, Non-Steroidal; D012997:Solvents; D009288:Naproxen; D007052:Ibuprofen