Hinge Binding
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.
DFG-Out Model
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.