Journal
JOURNAL OF MEDICINAL CHEMISTRY
Volume 58, Issue 1, Pages 252-264Publisher
AMER CHEMICAL SOC
DOI: 10.1021/jm5009264
Keywords
-
Categories
Funding
- Jurgen Manchot Foundation, Dusseldorf, Germany
Ask authors/readers for more resources
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 structureactivity 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
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available