The discovery of novel protein kinase inhibitors by using fragment-based high-throughput x-ray crystallography.
This article describes the application of a high-throughput X-ray crystallographic fragment-based screening methodology to identify low-molecular-weight leads for structure-based optimisation into protein kinase inhibitors. The identification of two novel p38alpha MAP kinase inhibitors (with IC50=65 and 150 nM) starting from low-molecular-weight fragments is described.
Gill
Adrian
A
Astex Technology, 436 Cambridge Science Park, Milton Road, Cambridge, CB4 0QA, UK. a.gill@astex-technology.com
Cleasby
Anne
A
Jhoti
Harren
H
D018360:Crystallography, X-Ray; D004353:Drug Evaluation, Preclinical / Q000295:instrumentation / Q000379:methods*; D006801:Humans; D048308:Mitogen-Activated Protein Kinase 14 / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D010446:Peptide Fragments / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000737:chemistry* / Q000494:pharmacology*
D010446:Peptide Fragments; D047428:Protein Kinase Inhibitors; D048308:Mitogen-Activated Protein Kinase 14