title: Computational selection of inhibitors of Abeta aggregation and neuronal toxicity.
abstract: Alzheimer's disease (AD) is characterized by the cerebral accumulation of misfolded and aggregated amyloid-beta protein (Abeta). Disease symptoms can be alleviated, in vitro and in vivo, by 'beta-sheet breaker' pentapeptides that reduce plaque load. However the peptide nature of these compounds, made them biologically unstable and unable to penetrate membranes with high efficiency. The main goal of this study was to use computational methods to identify small molecule mimetics with better drug-like properties. For this purpose, the docked conformations of the active peptides were used to identify compounds with similar activities. A series of related beta-sheet breaker peptides were docked to solid state NMR structures of a fibrillar form of Abeta. The lowest energy conformations of the active peptides were used to design three dimensional (3D)-pharmacophores, suitable for screening the NCI database with Unity. Small molecular weight compounds with physicochemical features and a conformation similar to the active peptides were selected, ranked by docking and biochemical parameters. Of 16 diverse compounds selected for experimental screening, 2 prevented and reversed Abeta aggregation at 2-3microM concentration, as measured by Thioflavin T (ThT) fluorescence and ELISA assays. They also prevented the toxic effects of aggregated Abeta on neuroblastoma cells. Their low molecular weight and aqueous solubility makes them promising lead compounds for treating AD.
authors.affiliation: Sealy Center for Structural Biology and Molecular Biophysics, Department of Biochemistry and Molecular Biology, UTMB, Galveston, TX 77555-0857, USA.
authors.forename: Deliang
authors.initials: D
authors.lastname: Chen
authors.forename: Zane S
authors.initials: ZS
authors.lastname: Martin
authors.forename: Claudio
authors.initials: C
authors.lastname: Soto
authors.forename: Catherine H
authors.initials: CH
authors.lastname: Schein
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy; D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism*; D000818:Animals; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D003198:Computer Simulation; D016208:Databases, Factual; D015195:Drug Design; D006801:Humans; D051379:Mice; D008958:Models, Molecular; D015394:Molecular Structure; D009474:Neurons / Q000166:cytology / Q000187:drug effects*; D010455:Peptides / Q000737:chemistry* / Q000494:pharmacology* / Q000633:toxicity; D011485:Protein Binding; D017433:Protein Structure, Secondary
chemical_list: D016229:Amyloid beta-Peptides; D010455:Peptides