Application of fragment screening by X-ray crystallography to β-secretase

…, G Chessari, A Cleasby, M Congreve…

Index: Howard, Nigel; Abell, Chris; Blakemore, Wendy; Chessari, Gianni; Congreve, Miles; Howard, Steven; Jhoti, Harren; Murray, Christopher W.; Seavers, Lisa C. A.; Van Montfort, Rob L. M. Journal of Medicinal Chemistry, 2006 , vol. 49, # 4 p. 1346 - 1355

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Citation Number: 125

Abstract

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 as 2-aminoquinoline), a piperidine, or an aliphatic hydroxyl group. The fragment hits were weak inhibitors of BACE-1 in the millimolar range ...