title: Discovery, biological evaluation, and crystal structure of a novel nanomolar selective butyrylcholinesterase inhibitor.
abstract: Butyrylcholinesterase (BChE) is regarded as a promising drug target as its levels and activity significantly increase in the late stages of Alzheimer's disease. To discover novel BChE inhibitors, we used a hierarchical virtual screening protocol followed by biochemical evaluation of 40 highest scoring hit compounds. Three of the compounds identified showed significant inhibitory activities against BChE. The most potent, compound 1 (IC50 = 21.3 nM), was resynthesized and resolved into its pure enantiomers. A high degree of stereoselective activity was revealed, and a dissociation constant of 2.7 nM was determined for the most potent stereoisomer (+)-1. The crystal structure of human BChE in complex with compound (+)-1 was solved, revealing the binding mode and providing clues for potential optimization. Additionally, compound 1 inhibited amyloid β(1-42) peptide self-induced aggregation into fibrils (by 61.7% at 10 μM) and protected cultured SH-SY5Y cells against amyloid-β-induced toxicity. These data suggest that compound 1 represents a promising candidate for hit-to-lead follow-up in the drug-discovery process against Alzheimer's disease.
authors.affiliation: Faculty of Pharmacy, University of Ljubljana , Aškerčeva 7, 1000 Ljubljana, Slovenia.
authors.forename: Boris
authors.initials: B
authors.lastname: Brus
authors.forename: Urban
authors.initials: U
authors.lastname: Košak
authors.forename: Samo
authors.initials: S
authors.lastname: Turk
authors.forename: Anja
authors.initials: A
authors.lastname: Pišlar
authors.forename: Nicolas
authors.initials: N
authors.lastname: Coquelle
authors.forename: Janko
authors.initials: J
authors.lastname: Kos
authors.forename: Jure
authors.initials: J
authors.lastname: Stojan
authors.forename: Jacques-Philippe
authors.initials: JP
authors.lastname: Colletier
authors.forename: Stanislav
authors.initials: S
authors.lastname: Gobec
mesh_terms: D016229:Amyloid beta-Peptides / Q000737:chemistry; D000818:Animals; D002091:Butyrylcholinesterase / Q000737:chemistry*; D045744:Cell Line, Tumor; D002800:Cholinesterase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002851:Chromatography, High Pressure Liquid; D003460:Crystallization; D055808:Drug Discovery; D006801:Humans; D051379:Mice; D062105:Molecular Docking Simulation; D010446:Peptide Fragments / Q000737:chemistry; D066329:Protein Aggregates; D013237:Stereoisomerism
chemical_list: D016229:Amyloid beta-Peptides; D002800:Cholinesterase Inhibitors; D010446:Peptide Fragments; D066329:Protein Aggregates; C075222:amyloid beta-protein (1-42); D002091:Butyrylcholinesterase