How Ligands Interact with the Kinase Hinge

ATP-competitive kinase inhibitors form hydrogen bond
interactions
with the kinase hinge region at the adenine binding site. Thus, it
is crucial to explore hinge-ligand recognition as part of a rational
drug design strategy. Here, harnessing known ligand-bound kinase structures
and experimental assay resources, we first created a kinase structure-assay
database (KSAD) containing 2705 nM ligand-bound kinase complexes.
Then, using KSAD, we systematically investigate hinge-ligand binding
patterns using interaction fingerprints, thereby delineating 15 different
hydrogen-bond interaction modes. We believe these results will be
valuable for de novo drug design and/or scaffold
hopping of kinase-targeted drugs.