Toward a pharmacophore for kinase frequent hitters.
Small molecule protein kinase inhibitors are widely employed as biological reagents and as leads in the design of drugs for a variety of diseases. One of the hardest challenges in kinase inhibitor design is achieving target selectivity. By utilizing X-ray structural information for four promiscuous inhibitors, we propose a five-point pharmacophore for kinase frequent hitters, demonstrate its ability to discriminate between frequent hitters and selective ligands, and suggest a strategy for selective inhibitor design.
Aronov
Alex M
AM
Vertex Pharmaceuticals Inc., Cambridge, Massachusetts 02139-4242, USA. alex_aronov@vrtx.com
Murcko
Mark A
MA
D018360:Crystallography, X-Ray; D008024:Ligands; D008958:Models, Molecular; D015394:Molecular Structure; D047428:Protein Kinase Inhibitors / Q000737:chemistry*; D011494:Protein Kinases / Q000737:chemistry*; D021281:Quantitative Structure-Activity Relationship
D008024:Ligands; D047428:Protein Kinase Inhibitors; D011494:Protein Kinases