IN SILICO DESIGN AND MOLECULAR DYNAMICS EVALUATION OF 2-ARYL-SUBSTITUTED BENZOXAZOLE DERIVATIVES AS POTENTIAL EPIDERMAL GROWTH FACTOR RECEPTOR TYROSINE KINASE INHIBITORS

Abstract

Objective: The epidermal growth factor receptor (EGFR) is a clinically established molecular target that plays a key role in the initiation and progression of multiple human cancers. This study aimed to rationally design and evaluate a series of 2-aryl-substituted benzimidazole, benzothiazole, and benzoxazole derivatives as potential EGFR tyrosine kinase inhibitors using an integrated in silico approach. Methods: Molecular docking studies were performed to investigate the binding affinities and interaction patterns of the designed compounds within the ATP-binding pocket of EGFR, using erlotinib as the reference inhibitor. The highest-ranked compounds were subsequently subjected to 100 ns molecular dynamics (MD) simulations to evaluate ligand-binding stability and dynamic conformational changes. Free energy landscape (FEL) analysis was performed to assess the thermodynamic stability of the ligand–EGFR complexes. Computational absorption, distribution, metabolism, excretion, and toxicity (ADMET) and drug-likeness analyses were also conducted to evaluate the physicochemical and predicted pharmacokinetic properties of the selected compounds. Results: Several designed compounds exhibited docking scores comparable to or exceeding those of erlotinib, with benzimidazole and benzothiazole derivatives showing particularly favorable binding orientations and conserved interactions with key catalytic residues. The 100 ns MD simulations demonstrated that benzimidazole-7 and benzothiazole-6 formed stable complexes with EGFR, characterized by low backbone root mean square deviation, reduced residue-level flexibility, persistent hydrogen bonding, and maintained structural compactness. FEL analysis further supported the stability of these complexes by identifying well-defined low-energy conformational states. In contrast, benzoxazole-6 exhibited greater conformational variability and reduced interaction persistence. ADMET and drug-likeness analyses indicated that the selected compounds possessed favorable physicochemical characteristics, complied with Lipinski’s and Veber’s rules, showed high predicted gastrointestinal absorption, and maintained acceptable predicted pharmacokinetic profiles. Conclusion: The integrated docking, MD, free energy, and ADMET analyses identify benzimidazole-7 and benzothiazole-6 as promising lead candidates for EGFR inhibition. These findings provide a robust computational foundation for further experimental validation through in vitro EGFR kinase inhibition and anticancer assays.