title: Discovery and Structure-Activity Relationships of a Highly Selective Butyrylcholinesterase Inhibitor by Structure-Based Virtual Screening.
abstract: Structure-based virtual screening of two libraries containing 567 981 molecules was used to discover novel, selective BuChE inhibitors, which are potentially superior symptomatic treatments in late-stage Alzheimer's disease. Compound 16 was identified as a highly selective submicromolar inhibitor of BuChE (huBuChE IC50 = 0.443 μM) with high permeability in the PAMPA-BBB model. The X-ray crystal structure of huBuChE in complex with 16 revealed the atomic-level interactions and offers opportunities for further development of the series.
authors.affiliation: School of Pharmacy, The University of Queensland , Brisbane, Queensland 4072, Australia.
authors.forename: Satish N
authors.initials: SN
authors.lastname: Dighe
authors.affiliation: School of Pharmacy, The University of Queensland , Brisbane, Queensland 4072, Australia.
authors.forename: Girdhar Singh
authors.initials: GS
authors.lastname: Deora
authors.affiliation: Institut de Biologie Structurale (IBS), Université Grenoble Alpes, CEA, CNRS, 38044 Grenoble, France.
authors.forename: Eugenio
authors.initials: E
authors.lastname: De la Mora
authors.affiliation: Département de Toxicologie et Risques Chimiques, Institut de Recherche Biomédicale des Armées , 91223 Brétigny sur Orge, France.
authors.forename: Florian
authors.initials: F
authors.lastname: Nachon
authors.affiliation: School of Pharmacy, The University of Queensland , Brisbane, Queensland 4072, Australia.
authors.forename: Stephen
authors.initials: S
authors.lastname: Chan
authors.affiliation: School of Pharmacy, The University of Queensland , Brisbane, Queensland 4072, Australia.
authors.forename: Marie-Odile
authors.initials: MO
authors.lastname: Parat
authors.affiliation: Département de Toxicologie et Risques Chimiques, Institut de Recherche Biomédicale des Armées , 91223 Brétigny sur Orge, France.
authors.forename: Xavier
authors.initials: X
authors.lastname: Brazzolotto
authors.affiliation: School of Pharmacy, The University of Queensland , Brisbane, Queensland 4072, Australia.
authors.forename: Benjamin P
authors.initials: BP
authors.lastname: Ross
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy* / Q000378:metabolism; D002091:Butyrylcholinesterase / Q000378:metabolism*; D002800:Cholinesterase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery; D004353:Drug Evaluation, Preclinical; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D013329:Structure-Activity Relationship
chemical_list: D002800:Cholinesterase Inhibitors; D002091:Butyrylcholinesterase