A pharmacophore map of small molecule protein kinase inhibitors

Protein kinases have emerged as one of the major drug target classes that are amenable to the development of small molecule inhibitors. They share a conserved structural similarity in the region of the ATP binding site, where most inhibitors interact. Using a pharmacophore approach, we have explored the features of protein-ligand interactions for a set of 220 kinase crystal structures from the Protein Data Bank (PDB). The resulting "pharmacophore map" shows the interactions made by all ligands with their receptors simultaneously. This gives insight that has been applied in the design of kinase screening sets and combinatorial libraries. An algorithm is described that scores small molecule structures for goodness of fit to the resulting binding site description obtained from the analysis. The algorithm identifies a pose that is close to the crystal structure pose for the majority of ligands, with only the 2D chemical structure as input and no knowledge of the crystal structure from which it was derived. Application of the algorithm to a test screening set gave a useful enrichment of active compounds.