Structural-Based Design of ErbB-2 Selective Small Molecule Kinase Inhibitors

摘要

During the first year, this task has been successfully completed. A summary on this task has been included in the 2001 Annual Report submitted to the DOD. We have used three template protein structures all with high resolution to model the active conformations of erbB-2 and EGFR. These template protein structures include the structure of the kinase domain of the insulin receptor kinase bound to an ATP analog and a peptide substrate, which was determined with X-ray crystallography to an accuracy of 1.9 A (PDB code: lIR3), the kinase domain of the human FGFRl, either alone or in the complex with a small molecule kinase inhibitor SU4984, or SU5402, or PDl73074, whose structures were determined with X-ray crystallography to an accuracy of from 2.0 to 2.5 A (PDB codes: lFGK, lAGW, lFGI and 2FGI), and the structure of the human tyrosine protein C (SRC), whose structure was determined with X-ray crystallography to an accuracy of 1.5 A (PDB code: lFMK). These proteins share the highest degree of homology with erbB-2 and EGFR in their kinase domains among all the structures in the Protein Databank (PDB). We have then performed extensive refinement of these modeled structures of erbB-2 and EGFR through molecular dynamics simulations using the CHARMM program and its latest version of the force field in explicit water environment.