CORES:  An Automated Method for Generating Three-Dimensional Models of Protein/Ligand Complexes

We describe a new, automated method for building 3D models of small-molecule ligands complexed with proteins. Modeling templates are constructed from frameworks (i.e., ring systems and linkers) of ligands extracted from 3D structures of ligands complexed with proteins that are structurally related to the target protein. These templates are typically substructures of the target ligand and are used to build models that constrain the ligand's conformation and binding orientation in the active site of the target protein. The practical utility of the method is shown by demonstrating that most ligands containing related frameworks bind protein kinases in the same orientation. Moreover, models for 15 of 19 cdk2/ligand complexes in the protein data bank built using our method deviate from the X-ray structure by less than 2 Å (rms). Finally, we show that over 70% of small-molecule protein kinase inhibitors published in J. Med. Chem. since 1993 can be modeled using a template extracted from a 3D protein kinase structure in the protein data bank.