title: Discovery of acetylcholinesterase peripheral anionic site ligands through computational refinement of a directed library.
abstract: The formation of beta-amyloid plaques in the brain is a key neurodegenerative event in Alzheimer's disease. Small molecules capable of binding to the peripheral anionic site of acetylcholinesterase (AChE) have been shown to inhibit the AChE-induced aggregation of the beta-amyloid peptide. Using the combination of a computational docking model and experimental screening, five compounds that completely blocked the amyloidogenic effect of AChE were rapidly identified from an approximately 200-member library of compounds designed to disrupt protein-protein interactions. Critical to this docking model was the inclusion of two explicit water molecules that are tightly bound to the enzyme. Interestingly, none of the tested compounds inhibited the related enzyme butyrylcholinesterase (BuChE) up to their aqueous solubility limits. These compounds are among the most potent inhibitors of amyloid beta-peptide aggregation and are equivalent only to propidium, a well-characterized AChE peripheral anionic site binder and aggregation inhibitor.
authors.affiliation: Department of Chemistry, Molecular Biology and The Skaggs Institute for Chemical Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA.
authors.forename: Tobin J
authors.initials: TJ
authors.lastname: Dickerson
authors.forename: Albert E
authors.initials: AE
authors.lastname: Beuscher
authors.forename: Claude J
authors.initials: CJ
authors.lastname: Rogers
authors.forename: Mark S
authors.initials: MS
authors.lastname: Hixon
authors.forename: Noboru
authors.initials: N
authors.lastname: Yamamoto
authors.forename: Yang
authors.initials: Y
authors.lastname: Xu
authors.forename: Arthur J
authors.initials: AJ
authors.lastname: Olson
authors.forename: Kim D
authors.initials: KD
authors.lastname: Janda
mesh_terms: D000110:Acetylcholinesterase / Q000737:chemistry* / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000737:chemistry*; D000838:Anions; D001665:Binding Sites; D002800:Cholinesterase Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D019295:Computational Biology; D019020:Directed Molecular Evolution; D008024:Ligands; D008958:Models, Molecular; D010446:Peptide Fragments / Q000737:chemistry*
chemical_list: D016229:Amyloid beta-Peptides; D000838:Anions; D002800:Cholinesterase Inhibitors; D008024:Ligands; D010446:Peptide Fragments; C078592:amyloid beta-protein (1-40); D000110:Acetylcholinesterase