In silico and in vitro tudies for identification of novel egfr tyrosine kinase inhibitors
Abstract
Epidermal growth factor receptor (EGFR) has been identified as a promising target in the treatment of non-small cell lung cancer (NSCLC). Mutations, including L858R/T790M double and L858R/T790M/C797S triple mutations, in the TK domain of EGFR have been linked to the severity of several cancers, especially NSCLC. A combination of comprehensive molecular modeling and in vitro kinase inhibition assay was used to unravel the mutational effects of EGFR on the susceptibility of five commercial drugs (erlotinib, gefitinib, afatinib, dacomitinib, and osimertinib) from each generation of EGFR in comparison with the wild-type EGFR. The binding affinity of five-FDA-approved drugs towards the L858R/T790M and L858R/T790M/C797S EGFR mutations was in good agreement with the experimental data, ranked in the order of osimertinib > afatinib > dacomitinib > erlotinib > gefitinib. Three hot-spot residues at the hinge region (M790, M793, and C797) were involved in the binding of osimertinib, enhancing their inhibitory activity towards mutated EGFRs. Erlotinib/mutant EGFR resistance is mainly caused by the low number of surrounding atoms, and the high number of water molecules accessible. This work paves the way for further design and discovery of novel EGFR inhibitors to overcome drug resistance mechanisms. Even though several commercial drug targeting EGFR has been reported, acquired drug resistance caused by the EGFR mutation develops inevitably after long-term treatment. Consequently,…
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