In Silico Design, Molecular Docking, Molecular Dynamics Simulation, and ADMET Evaluation of Novel Quinazoline Derivatives as EGFR Inhibitors for Non-Small-Cell Lung Cancer

Abstract

Lung cancer continues to be one of the biggest killers of cancer patients in the world, and constant development of safer and effective targeted therapies is still required. In this study, the rational design and computational assessment of novel quinazoline-based ligands as inhibitors of the epidermal growth factor receptor (EGFR), which is an important therapeutic target in non-small-cell lung cancer (NSCLC), is investigated. Ten novel quinazoline derivatives (QZ-01 to QZ-10) were designed by structurally modifying the 4-anilinoquinazoline scaffold. To identify binding affinities and poses, 100 ns molecular dynamics (MD) simulations were performed with GROMACS on the top docked complexes, and molecular docking was carried out with AutoDock Vina. Root Mean Square Deviation (RMSD), Root Mean Square Fluctuation (RMSF), radius of gyration (Rg), hydrogen-bond occupancy, and MM-GBSA binding free-energy calculations were used to comprehensively evaluate the stability of the complexes. Besides, SwissADME and pkCSM were used for drug-likeness prediction and pharmacokinetic (ADMET) properties prediction. The docking score from the results shows that the three compounds (QZ-08, QZ-07, and QZ-04) had a score of −9.82, −9.68, and −9.56 kcal/mol respectively, better than the reference drug erlotinib with a score of −8.73 kcal/mol. QZ-08 had the lowest average RMSD and RMSF of 1.82 Å and 0.74 Å respectively, and hydrogen-bond occupancy of 93.2% along with MM-GBSA binding energy of −63.15 kcal/mol compared to those of erlotinib as −48.73 kcal/mol during MD simulations. QZ-07 also showed strong structural stability and good binding affinity to key residues in EGFR such as Met793, Lys745, Asp855, and Cys797. Both candidates were calculated to have high gastrointestinal absorption and strict compliance with Lipinski's Rule of Five (RO5) with no AMES mutagenicity and minor cardiotoxicity. This computational workflow was integrated and allowed the evaluation of binding strength, conformational stability, pharmacokinetic suitability and safety simultaneously. Finally, QZ-08 and QZ-07 are extremely promising computational leads that are suggested for further synthesis and biological evaluation as possible EGFR targeted anticancer agents.

Keywords: Quinazoline Derivatives; Epidermal Growth Factor Receptor (EGFR); Non-Small-Cell Lung Cancer (NSCLC); Molecular Docking; Molecular Dynamics Simulation.