Progress in Structure-Based Design of EGFR Inhibitors

Epidermal growth factor receptors (EGFRs) belong to the ErbB family of receptor tyrosine kinases (TKs) involved in the proliferation of normal and malignant cells. As mutations and overexpression of ErbB TKs are implicated in carcinoma and glioblastoma and are related to both a very strong resistance to chemotherapy and a poor survival means that ErbB receptors are targets of considerable importance for anti-cancer drug design. Besides using monoclonal antibodies for anti-EGFR-related cancer therapeutics, small molecules - tyrosine kinase inhibitors are being considered as well. Some of these therapies have entered clinical trials or have been approved for clinical use. Based on experimental methods (radiometry, immunofluoroscence or luminescence, electrophoresis) that are mainly employed for measuring and interpreting the selectivity of protein kinase inhibitors, routine accomplishment of selectivity of small molecules for particular protein kinases is a substantial challenge. In light of this, we herein elaborate a computer-based protein engineering approach demonstrating its potential to be a viable supplement to experiment in modulating the affinity of ligand molecules for EGFR in an efficient manner. The structural basis of the remarkable strategy is also elucidated using our recent results obtained by means of molecular docking and molecular dynamics simulations. A few critical implications for successful structure-based design of prospective drug candidates against EGFR-related cancers are consequently discussed.