Virtual screening for kinase targets.
Kinases have become a major area of drug discovery and structure-based design. Hundreds of 3D structures for more than thirty different kinases are available to the public. High structural and sequence homology within the kinase gene family makes the remaining kinases ideal targets for homology modeling and virtual screening. Somewhat surprisingly, however, the number of publications about virtual screening of kinases is very low. Therefore, rather than reviewing the field of virtual screening for kinases, we attempt here a hybrid approach of presenting what is known and common practice together with new studies on CDK2 and SRC kinase. To illustrate the challenges and pitfalls of virtual screening for kinase targets we focus on the question of how ranking is influenced by the database screened, the docking scheme, the scoring function, the activity of the compounds used for testing, and small changes in the binding pocket. In addition, a case study of finding irreversible inhibitors of ErbB2 through in silico screening is presented.
Muegge
Ingo
I
Boehringer Ingelheim Pharmaceuticals, Inc, 900 Ridgebury Road, Ridgefield, CT 06877-0368, USA. imugge@rdg.boehringer-ingelheim.com
Enyedy
Istvan J
IJ
D001665:Binding Sites; D030562:Databases, Protein; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000737:chemistry; D008024:Ligands; D008958:Models, Molecular; D011485:Protein Binding; D047428:Protein Kinase Inhibitors; D011494:Protein Kinases / Q000737:chemistry*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000737:chemistry; D013329:Structure-Activity Relationship
D004791:Enzyme Inhibitors; D008024:Ligands; D047428:Protein Kinase Inhibitors; D011494:Protein Kinases; D018719:Erb-b2 Receptor Tyrosine Kinases