In Silico Molecular Docking, Molecular Dynamics Simulation, and Pharmacokinetic prediction of Novel N-(2-(4-oxo-2-phenyl quinazoline-3(4H)-yl) Derivatives with Enhanced Anti-proliferative Activity

Abstract

The design of novel Quinazoline derivatives with integrated molecular modeling techniques; molecular docking, MD simulations, and ADME-T profiling-features within medicinal chemistry have a great goal in overcoming drug resistance and reducing toxicity in cancer therapy by developing selective, potent, and nontoxic anti-proliferative agents. Molecular docking studies of synthesized ligands with EGFR were analyzed against erlotinib as the reference ligand. From the studies, it was observed that seven assayed ligands showed higher binding affinities compared to erlotinib, which can be reflected by higher PLP fitness scores and crucial interactions with active site essential residues like ASP831 and THR766. The stability of the ligand-receptor complex was reaffirmed by molecular dynamics simulation on the top-performing ligand. The analyses on RMSD and RMSF displayed slight structural deviations along the course of the 25-ns simulation, showing the ligand was strongly stable within the EGFR active site. The other interactions with key residues of EGFR were generally the same, so it is concluded that the ligand can act as a stable anti-proliferating agent. The ADME-T predictions indicated that all the designed ligands fulfilled Lipinski's Rule of Five, hence suggesting favorable drug-likeness. Human oral absorption for these compounds was high; this enhanced their clinical potential. The present work underlines the importance of in silico approaches when designing and conducting a study on new anti-proliferative agents. This research combined molecular docking with molecular dynamics and ADME-T profiling to identify potential lead compounds with enhanced binding affinities and also with favorable pharmacokinetic properties. Further experimental studies have to be conducted for confirmation to have therapeutic applications in the treatment of cancer.