Comprehensive analysis and outcomes of hybridization of physiologically active heterocycles targeting epidermal growth factor receptor (EGFR).

Epidermal growth factor receptors (EGFR) are primarily engaged in the regulation of fundamental cellular processes. Overexpression and mutations in these tyrosine kinases cause a variety of malignancies, including lung cancer. The current study addresses the suppression of inactive and mutant variants of the EGFR target site via two primary proposals: (1) To prevent the formation of its mutant form by inhibiting inactive EGFR. (2) To suppress the mutant EGFR directly. After the virtual screening of a newly designed series of hybrid models, selected molecules were synthesized and well-characterized from various spectroscopic and spectrometric methods. The critical analysis and chemistry behind the structural interactions of the selected compounds with three target sites were discussed i.e., inactive EGFR (PDB code: 1XKK), mutant EGFR (PDB code: 3W2O), and allosteric site of mutant EGFR (PDB code: 6P1L). It was observed that compound 7 showed effective results in terms of docking score, structural interactions as well as orientation in the binding pocket towards the inactive target site. Whereas, compound 8 exhibited all the above-mentioned features excellently against mutant EGFR. Apart from that, the investigations were expanded to study the structural behaviour in the allosteric site, where compound 8 once again performed effectively. Such proposals were further clarified by running molecular dynamics (MD) simulation for 100 ns towards inactive, mutant, and allosteric sites of mutant EGFR. Where compounds 7, and 8 demonstrated highly consistence behaviour during the whole simulation trajectory. Further, in vitro results of EGFR inhibition assay and anti-proliferative activity were found in accordance with the computational findings. For the EGFR inhibition assay, compounds 7, and 8 showed excellent IC50 values of 20.7, and 22.5 μM respectively. Moreover, IC50 values exhibited by both the compounds in anti-proliferative activity were observed to be 27.5, and 11.7 μM respectively. Thus, compounds 7 and 8 may have potential to become good anticancer agents.