Benzoin-Based Bis-Pyrrole Carbonitriles as Targeted EGFR Inhibitors: Insights from DFT Calculations, Molecular Docking, and Pharmacokinetic Profiling

Abstract

This study examined four previously synthesized and structurally characterized bispyrrole derivatives to evaluate their potential interactions with the epidermal growth factor receptor (EGFR) and to explore the correlation between molecular structure, electronic properties, and predicted drug-likeness. An integrated computational workflow was applied, combining molecular docking, density functional theory (DFT), and in silico ADMET analysis. Docking simulations were performed against the EGFR tyrosine kinase domain (PDB ID: 1M17), utilizing erlotinib as a reference inhibitor. Redocking of the co-crystallized ligand yielded a root-mean-square deviation (RMSD) of 0.8627 Å, confirming the reliability of the protocol in reproducing the experimental binding pose. Among the evaluated derivatives, compound 2 achieved the most favorable docking score (-9.521 kcal/mol), surpassing erlotinib (-8.24 kcal/mol), with predicted interactions involving LYS721, HIS781, and LEU694. DFT calculations executed at the B3LYP/6-31G level revealed that compound 2 possessed the narrowest HOMO-LUMO gap (3.3423 eV), indicating enhanced electronic reactivity within the series. Conversely, compound 1 displayed the widest energy gap (4.2945 eV) along with a more favorable predicted drug-likeness profile and a bioavailability score of 0.55. ADMET predictions identified notable limitations concerning molecular weight, lipophilicity, potential cytochrome P450 inhibition, and projected toxicity. These findings demonstrate that high docking affinity does not strictly parallel favorable pharmacokinetic properties. In conclusion, compound 2 emerges as a promising candidate for experimental follow-up, though its actual EGFR inhibitory activity and