title: Binding of nonsteroidal anti-inflammatory drugs to Abeta fibril.
abstract: Nonsteroidal anti-inflammatory drugs are considered as potential therapeutic agents against Alzheimer's disease. Using replica exchange molecular dynamics and atomistic implicit solvent model, we studied the mechanisms of binding of naproxen and ibuprofen to the Abeta fibril derived from solid-state NMR measurements. The binding temperature of naproxen is found to be almost 40 K 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 with those bound to the convex edge. Our simulations appear to provide microscopic rationale for the differing binding affinities of naproxen and ibuprofen observed experimentally.
authors.affiliation: Department of Bioinformatics and Computational Biology, George Mason University, Manassas, Virginia 20110, USA.
authors.forename: Takako
authors.initials: T
authors.lastname: Takeda
authors.forename: Wenling E
authors.initials: WE
authors.lastname: Chang
authors.forename: E Prabhu
authors.initials: EP
authors.lastname: Raman
authors.forename: Dmitri K
authors.initials: DK
authors.lastname: Klimov
mesh_terms: D000595:Amino Acid Sequence; D016229:Amyloid beta-Peptides / Q000737:chemistry* / Q000378:metabolism; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000737:chemistry / Q000378:metabolism; D001665:Binding Sites; D001667:Binding, Competitive; D003198:Computer Simulation; D006801:Humans; D007052:Ibuprofen / Q000737:chemistry* / Q000378:metabolism; D007700:Kinetics; D008958:Models, Molecular; D008969:Molecular Sequence Data; D015394:Molecular Structure; D009288:Naproxen / Q000737:chemistry* / Q000378:metabolism; D011485:Protein Binding; D011487:Protein Conformation; D017434:Protein Structure, Tertiary; D013696:Temperature
chemical_list: D016229:Amyloid beta-Peptides; D000894:Anti-Inflammatory Agents, Non-Steroidal; D009288:Naproxen; D007052:Ibuprofen