Developing novel allosteric inhibitors

In order to develop novel non-ATP binding site or allosteric binding site directed inhibitors, 3D structure-based drug design provides a key strategy to generate promising lead compounds. Protein kinase drug discovery will exploit a variety of high-powered in silico tools to visualize, analyze, and probe the molecular properties and interactions of novel small-molecule inhibitors with possible allosteric binding sites. Integration of in silico tools (e.g., molecular modeling and virtual screening) with structural biology (e.g., X-ray and/or NMR proven structures of a lead compound complexed with its therapeutic target), chemical synthesis, biological screening (e.g., biochemical kinase assays with kinetic analysis, in vitro and in vivo assays), cheminformatics, and bioinformatics provides the background for novel non-ATP binding site directed or allosteric kinase inhibitor drug discovery. The use of an allosteric inhibitory library for hit finding on various kinase targets could be a very important (first) step.for the required structural biological studies.