title: Comprehensive analysis of three-dimensional activity cliffs formed by kinase inhibitors with different binding modes and cliff mapping of structural analogues.
abstract: Kinases are among the structurally most extensively characterized therapeutic targets. For many kinases, X-ray structures of inhibitor complexes are publicly available. We have identified all three-dimensional activity cliffs (3D-cliffs) formed by kinase inhibitors. More than 1300 X-ray structures of unique kinase-inhibitor complexes and associated activity data were analyzed. On the basis of binding mode comparison and 3D similarity calculations, 105 3D-cliffs were detected for type I, type II, or type III inhibitors of 13 different kinases. Many of these activity cliffs revealed clear interaction differences between highly and weakly potent inhibitors. More than 200 structural analogues of 3D-cliff compounds were identified whose structure-activity relationships (SARs) can be further explored in three dimensions on the basis of the corresponding 3D-cliffs. In addition to SAR exploration, 3D-cliffs provide useful interaction hypotheses for structure-based design. The kinase inhibitor and activity cliff information is made freely available as a part of our study.
authors: Department of Life Science Informatics, B-IT, LIMES Program Unit Chemical Biology and Medicinal Chemistry, Rheinische Friedrich-Wilhelms-Universität , Dahlmannstrasse 2, D-53113 Bonn, Germany.
authors: Norbert
authors: N
authors: Furtmann
authors: Ye
authors: Y
authors: Hu
authors: Jürgen
authors: J
authors: Bajorath
mesh_terms: D000465:Algorithms; D018360:Crystallography, X-Ray; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D008958:Models, Molecular; D015394:Molecular Structure; D010770:Phosphotransferases / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000378:metabolism; D011485:Protein Binding; D025941:Protein Interaction Mapping / Q000379:methods; D017434:Protein Structure, Tertiary; D013329:Structure-Activity Relationship
chemical_list: D004791:Enzyme Inhibitors; D010770:Phosphotransferases