Bioinformatics-driven discovery of novel EGFR kinase inhibitors as anti-cancer therapeutics: In silico screening and in vitro evaluation

Epidermal growth factor receptor EGFR inhibitors are widely used as first line therapy for the treatment of non-small-cell lung cancer (NSCLC) in patients harboring EGFR mutation. However, the acquisition of a second-site mutation (T790 M) limited the efficacy and developed resistance. Therefore, discovery and development of specific drug target for this mutation is of urgent needs. In our study we used the ChemDiv diversity database for receptor-based virtual screening to secure EGFR-TK inhibitors chemotherapeutics. We identified four compounds that bind to the ATP-binding region of the EGFR-TK using AutoDock 4.0 and AutoDock Vina1.1.2 and post-docking investigations. The ligand showed hydrophobic interactions to the hydrophobic region of the binding site and engaged in hydrogen bonding with Met793. The ligands also explored π–cation interactions between the π-system of the ligand–phenyl ring and the positive amino group of Lys745. Molecular mechanics Poisson–Boltzmann surface area MM/PBSA per-residue energy decomposition analyses revealed that Val726, Leu792, Met793, Gly796, Cys797, Leu798, and Thr844 contributed the most to the binding energy. Biological evaluation of the retrieved hit compounds showed suppressing activity against EGFR auto phosphorylation and selective apoptosis-induced effects toward lung cancer cells harboring the EGFR L858R/T790M double mutation. Our work anticipated into novel and specific EGFR-TKIs and identified new compounds with therapeutic potential against lung cancer.