Induced-fit docking studies of the active and inactive states of protein tyrosine kinases.

Inhibition of tyrosine kinases (such as the epidermal growth factor receptor, EGFR, and/or Abelson leukemia virus protein kinase, ABL) represents a major advancement in the treatment of solid tumors, supported by the clinical administration of gefitinib, erlotinib, imatinib, and dasatinib. The identification of the binding interactions in the EGFR/ligands and the ABL/ligands complexes can facilitate the structure-based design of new tyrosine kinase inhibitors. We carried out induced-fit docking studies of 18 structurally diverse kinase inhibitors against the EGFR, the active and inactive states of the ABL protein. Our docking data show that the induced-fit docking (IFD) protocol can successfully reproduce the native poses of ligands from different sources. The binding interactions and the docked poses are consistent with the available experimental data. Our results indicate that imatinib is a weak binder to the active state of ABL but a strong binder to EGFR. The increased sensitivity of erlotinib to EGFR might be attributed to Cys797 of EGFR. In addition to Cys797, other important residues for kinase inhibitor design include Thr790, Met793, Lys745 and Asp855 of EGFR; and Thr315, Met318, Asp381 and Glu286 of the ABL. The minimum number of H-bonds required for the ligand binding provides a reasonable explanation to the effectiveness of nilotinib against most imatinib resistant mutants.