Docking simulations of receptor tyrosine kinase inhibitors: estimation of inhibition constants (Ki) of a series of experimentally tested compounds

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The Receptor Tyrosine Kinase (RTK) family in humans includes the epidermal growth factor receptor (EGFR, ErbB1, HER1), ErbB2 (HER2, Neu), ErbB3 (HER3), Insulin-growth factor receptor (IGFR), platelet derived growth factor receptors (PDGFR), vascular endothelial cell growth factor (VEGF) receptor, and fibroblast growth factor receptor (FGFR), each of which mediates cell growth, and differentiation events essential to the formation and maintenance of normal organisms. The amino acid sequences of the tyrosine kinase domains of RTKs are highly conserved ATP binding motif and substrate binding regions. These receptors have intrinsic tyrosine kinase activity that upon ligand binding and phosphorylation, interact with other proteins of the signaling cascade. Inappropriate activation of these receptors has been implicated in the progression of cancer and they are well-known targets for anti-cancer drugs. For example, overexpression of the ErbB2 receptor tyrosine kinase occurs in more than 30% of breast tumors and is associated with the most aggressive forms of the disease. Elucidation of the X-ray crystallographic structure of RTK family has opened the way for molecular modeling studies. Most small molecule inhibitors of RTKs are ATP competitive, by binding to the ATP-pocket of the kinase domain. However, the conserved ATP binding motif poses a major bottleneck for the discovery of highly specific inhibitors of individual RTKs. In this study, a series of experimentally tested model compounds has been docked computationally to the active site of the respective RTK binding pocket. The docking simulations were performed using AutoDock 3.0.5, FlexX, and DOCK 4.0 programs. The free energies of binding (DeltaG) and inhibition constants (Ki) of the docked compounds were calculated from the best docked lists selected from each docking program. For most cases, good correlation between the calculated and experimental Ki values was obtained. The inhibition constants obtained from each docking program were compared. These studies provide us with an important new approach for predicting the inhibition constants of newly designed and previously untested RTK inhibitors.