Hinge-binding library designs are validated by docking a minimally substituted scaffold into various different high-resolution kinase x-ray structures. These structures have been selected from across the phylogenetic tree to ensure broad coverage of tyrosine and serine/threonine kinases.
The BioFocus Kinase Toolkit™ provides a two-dimensional map (2D Roadmap) of the key ligand-binding features within a customized ATP-site model, allowing predictions of affinity, selectivity, and likely off-target issues based on the compositions of the individual sub-sites. This knowledge can then be used to select the appropriate side chains or monomers with which to decorate the scaffolds.
An approach to the design of kinase libraries with higher selectivity potential is to target the DFG-out allosteric pocket adjacent to the ATP site. BioFocus has developed a generalized binding model of the DFG-out pocket that enables the targeting of a range of inactive kinase conformations.