title: Application of fragment screening by X-ray crystallography to beta-secretase.
abstract: This paper describes an application of fragment screening to the aspartyl protease enzyme, beta-secretase (BACE-1), using high throughput X-ray crystallography. Three distinct chemotypes were identified by X-ray crystallography as binding to the catalytic aspartates either via an aminoheterocycle (such as 2-aminoquinoline), a piperidine, or an aliphatic hydroxyl group. The fragment hits were weak inhibitors of BACE-1 in the millimolar range but were of interest because most of them displayed relatively good ligand efficiencies. The aminoheterocycles exhibited a novel recognition motif that has not been seen before with aspartic proteases. Virtual screening around this motif identified an aminopyridine with increased potency and attractive growth points for further elaboration using structure-based drug design. The companion paper illustrates how sub-micromolar inhibitors were developed starting from this fragment.
authors.affiliation: Astex Therapeutics Ltd., 436 Cambridge Science Park, Milton Road, Cambridge CB4 0QA, United Kingdom. c.murray@astex-therapeutics.com
authors.forename: Christopher W
authors.initials: CW
authors.lastname: Murray
authors.forename: Owen
authors.initials: O
authors.lastname: Callaghan
authors.forename: Gianni
authors.initials: G
authors.lastname: Chessari
authors.forename: Anne
authors.initials: A
authors.lastname: Cleasby
authors.forename: Miles
authors.initials: M
authors.lastname: Congreve
authors.forename: Martyn
authors.initials: M
authors.lastname: Frederickson
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Hartshorn
authors.forename: Rachel
authors.initials: R
authors.lastname: McMenamin
authors.forename: Sahil
authors.initials: S
authors.lastname: Patel
authors.forename: Nicola
authors.initials: N
authors.lastname: Wallis
mesh_terms: D000634:Aminoquinolines / Q000737:chemistry; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D001665:Binding Sites; D018360:Crystallography, X-Ray; D006801:Humans; D008958:Models, Molecular; D010880:Piperidines / Q000737:chemistry; D011485:Protein Binding; D021281:Quantitative Structure-Activity Relationship; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry
chemical_list: D000634:Aminoquinolines; D010880:Piperidines; D011994:Recombinant Proteins; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human