Binding of non-steroidal anti-inflammatory drugs to Aβ fibril

• Published in: Proteins, structure, function, and bioinformatics structure, function, and bioinformatics, 2010-10, Vol.78 (13), p.2849-2860
• Main Authors: Takeda, Takako, Chang, Wenling E., Raman, E. Prabhu, Klimov, Dmitri K.
• Format: Article
• Language: English
• ISSN: 0887-3585; 1097-0134
• DOI: 10.1002/prot.22804

Non-steroidal anti-inflammatory drugs are considered as potential therapeutic agents against Alzheimer’s disease. Using REMD and atomistic implicit solvent model we studied the mechanisms of binding of naproxen and ibuprofen to the Aβ fibril derived from solid-state NMR measurements. The binding temperature of naproxen is found to be almost 40K higher than of ibuprofen implicating higher binding affinity of naproxen. The key factor, which enhances naproxen binding, is strong interactions between ligands bound to the surface of the fibril. The naphthalene ring in naproxen appears to provide a dominant contribution to ligand-ligand interactions. In contrast, ligand-fibril interactions cannot explain differences in the binding affinities of naproxen and ibuprofen. The concave fibril edge with the groove is identified as the primary binding location for both ligands. We show that confinement of the ligands to the groove facilitates ligand-ligand interactions that lowers the energy of the ligands bound to the concave edge compared to those bound to the convex edge. Our simulations appear to provide microscopic rationale for the differing binding affinities of naproxen and ibuprofen observed experimentally.