PREDICTION OF EGFR–QUINAZOLINE DRUG INTERACTIONS USING MOLECULAR DOCKING AND MOLECULAR DYNAMICS

Abstract

EGFR is a known target molecule in non-small cell lung cancer (NSCLC) and acquired resistance is still a challenge for EGFR-targeted therapy. Structural scaffold of quinazoline containing compounds are useful for structure based inhibition development. A computational approach involving ligand preparation, receptor preparation, binding-site definition, molecular docking, protein–ligand interaction analysis and molecular dynamics (MD) studies of the selected complexes was employed in this study to assess the twelve quinazoline-based compounds against EGFR. All 12 ligands could be successfully optimized, with molecular weights ranging from 284.28 to 418.05 g/mol, minimized energies from -8.84 to -17.77 kcal/mol, and net partial charges from -0.210 to +0.144. The docking scores were found to vary from −7.84 to −9.41 kcal/mol. QZ-12 showed the most favorable docking score (−9.41 kcal/mol), followed by QZ-05 (−9.28), QZ-10 (−9.12), and QZ-11 (−9.01). They were then chosen for dynamic evaluation, these four compounds. Predicted interactions include hydrogen bonding, hydrophobic, electrostatic and π-interactions with important EGFR residues such as Leu718, Val726, Ala743, Lys745, Thr790, Gln791, Leu792, Met793, Gly796, Leu844, Asp855 and Phe856. During the MD analysis, the lowest mean RMSD (1.46 Å) was obtained with QZ-12, while the lowest final RMSD (1.74Å), lowest mean RMSF (0.98Å), lowest radius of gyration (21.15Å) and highest interaction persistence (88.0%) were achieved with QZ-11. In general, the compounds QZ-12, QZ-11, QZ-05 and QZ-10 were determined as the most promising for further investigation. The results are computational predictions which need to be validated by experiments.