Gefitinib derivatives and drug-resistance: A perspective from molecular dynamics simulations

Epidermal-growth factor receptor (EGFR) is a transmembrane tyrosine kinase (TK) with a significant role in cell survival. EGFR is upregulated in various cancer cells and known as a druggable target. Gefitinib is a first-line TK inhibitor used against metastatic non-small cell lung cancer (NSCLC). Despite initial clinical response, a conserved therapeutic effect could not be achieved due to the occurrence of resistance mechanisms. Point mutations in EGFR genes are one of the major causes of rendered tumor sensitivity. To aid in the development of more efficient TKIs, chemical structures of prevailing drugs and their target binding patterns are very important. The aim of the present study was to propose synthetically-accessible gefitinib congeners with enhanced binding fitness to clinically frequent EGFR mutants. Docking simulations of intended molecules identified 1-(4-(3-chloro-4-fluorophenylamino)-7-methoxyquinazolin-6-yl)-3-(oxazolidin-2-ylmethyl) thiourea (23) as a top-binder structure inside G719S, T790 M, L858R and T790 M/L858R-EGFR active sites. Superior docked complexes were subjected to the entire 400 ns molecular dynamics (MD) simulations. Analysis of data revealed the stability of mutant enzymes upon binding to molecule 23. All mutant complexes with the exception of a T790 M/L858R-EGFR, were majorly stabilized through cooperative hydrophobic contacts. Pairwise analysis of H-bonds proved Met793 as the conserved residue with stable H-bond participations as hydrogen bond donor (Frequency 63-96%). Amino acid decomposition analysis confirmed the probable role of Met793 in complex stabilization. Estimated binding free energies indicated the proper accommodation of molecule 23 inside target active sites. Pairwise energy decompositions of stable binding modes revealed the energetic contribution of key residues. Although wet lab experiments are required to unravel the mechanistic details of mEGFR inhibition, MD results provide structural basis for those events that are difficult to address experimentally. The outputs of the current study may assist to design small molecules with high potency to mEGFRs.