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.
Keywords: Affinity, cancer, drug design, EGFR, inhibitor, kinase, protein engineering, single point mutation.
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