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J Med Chem. 2016 Jun 9;59(11):5356-67. doi: 10.1021/acs.jmedchem.6b00212. Epub 2016 May 20.

Exploitation of a Novel Binding Pocket in Human Lipoprotein-Associated Phospholipase A2 (Lp-PLA2) Discovered through X-ray Fragment Screening.

Author information

1
Astex Pharmaceuticals , 436 Cambridge Science Park, Milton Road, Cambridge CB4 0QA, United Kingdom.
2
GlaxoSmithKline , 709 Swedeland Road, King of Prussia, Pennsylvania 19406, United States.
3
Centre de Recherches Francois Hyafil, GlaxoSmithKline , 25-27 Avenue du Québec, Les Ulis, France.
4
GlaxoSmithKline , 1250 South Collegeville Road, Collegeville, Pennsylvania 19426, United States.
5
GlaxoSmithKline , Gunnels Wood Road, Stevenage SG1 2NY, United Kingdom.

Abstract

Elevated levels of human lipoprotein-associated phospholipase A2 (Lp-PLA2) are associated with cardiovascular disease and dementia. A fragment screen was conducted against Lp-PLA2 in order to identify novel inhibitors. Multiple fragment hits were observed in different regions of the active site, including some hits that bound in a pocket created by movement of a protein side chain (approximately 13 Å from the catalytic residue Ser273). Using structure guided design, we optimized a fragment that bound in this pocket to generate a novel low nanomolar chemotype, which did not interact with the catalytic residues.

PMID:
27167608
DOI:
10.1021/acs.jmedchem.6b00212
[Indexed for MEDLINE]

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