Application of Fragment Screening by X-ray Crystallography to β-Secretase
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...
Saved in:
Published in | Journal of medicinal chemistry Vol. 50; no. 6; pp. 1116 - 1123 |
---|---|
Main Authors | , , , , , , , , , |
Format | Journal Article |
Language | English |
Published |
Washington, DC
American Chemical Society
22.03.2007
|
Subjects | |
Online Access | Get full text |
Cover
Loading…
Summary: | 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 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. |
---|---|
Bibliography: | istex:9C14614D951896853C4917C9AA8BA2EE83DC5B5B ark:/67375/TPS-J4FTCDN2-C Coordinates for the β-secretase complexes with compounds 1−5 have been deposited in the Protein Data Bank under accession codes 2OHK, 2OHL, 2OHM, 2OHN, and 2OFO, together with the corresponding structure factor files. ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 |
ISSN: | 0022-2623 1520-4804 |
DOI: | 10.1021/jm0611962 |