Homology models of the mutated EGFR and their response towards quinazolin analogues

One of the most intensely studied tyrosine kinases is the epidermal growth factor receptor (EGFR). The tyrosine kinase receptors are known to be over expressed in some solid tumors and non-small cell lung cancers, causing differential susceptibility to the quinazoline inhibitors. In this study we have taken SYK tyrosine kinase coordinates from PDB database to model two new EGFR receptors with these mutations G695S and L834R and conducted all the docking studies of the inhibitors, also evaluated these two models for quality of structure using PROCHECK. Seven quinazoline analogues (gefitinib, erlotinib, CI-1033, and EKB-569 and other analogues) were selected for comparisons among the two new models. This study determined the receptor/inhibitor interactions, at that active domain binding sites consisting of 15 amino acids. We were able to calculate the energy data for each of the seven inhibitors. This data has been important in interpreting the affinity between the inhibitors evaluated against the three models of EGFR (wild-type and two mutated types). “Affinity”-based studies have indicated the order of response based on docking energy levels (Van der Waals and electrostatic interactions). The active ATP binding sites consisting of 15 amino acid residues were identified and the total energy (Etotal) which showed the affinity between the inhibitor molecules and the receptor (Van der Waals and electrostatic interactions). The selection of the quinazoline analogues was purely on their emergence as possible candidates in the drug discovery areas. This study describes the successful application of these models that we constructed for molecular docking studies to rationally design compounds predicted to bind favorably to the modeled EGFR catalytic sites.