Application of Fragment Screening by X-ray Crystallography to β-Secretase

• Published in: Journal of medicinal chemistry Vol. 50; no. 6; pp. 1116 - 1123
• Main Authors: Murray, Christopher W, Callaghan, Owen, Chessari, Gianni, Cleasby, Anne, Congreve, Miles, Frederickson, Martyn, Hartshorn, Michael J, McMenamin, Rachel, Patel, Sahil, Wallis, Nicola
• Format: Journal Article
• Language: English
• Published: Washington, DC American Chemical Society 22.03.2007
• Subjects: Aminoquinolines - chemistry; Amyloid Precursor Protein Secretases - antagonists & inhibitors; Amyloid Precursor Protein Secretases - chemistry; Aspartic Acid Endopeptidases - antagonists & inhibitors; Aspartic Acid Endopeptidases - chemistry; Binding Sites; Biological and medical sciences; Crystallography, X-Ray; Humans; Medical sciences; Miscellaneous; Models, Molecular; Pharmacology. Drug treatments; Piperidines - chemistry; Protein Binding; Quantitative Structure-Activity Relationship; Recombinant Proteins - antagonists & inhibitors; Recombinant Proteins - chemistry; virtual screening; Enzyme; Quinoline derivatives; Non peptide compound; Crystallography; X ray diffraction; Fragment; Amyloid precursor protein; Peptidases; Screening; Piperidine derivatives; Binding mode; β-secretase; Hydrolases; Aspartic endopeptidases

This paper describes an application of fragment screening to the aspartyl protease enzyme, β-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...