Design and In Silico Evaluation of Coumarin- Triazole Hybrids as EGFR Inhibitors: Molecular Docking and ADMET Analysis
Abstract
A series of coumarin-triazole hybrids (1a-1j) were designed and evaluated as Epidermal Growth Factor Receptor (EGFR) inhibitors using molecular docking and in silico pharmacokinetic analysis. Molecular docking was carried out against the EGFR tyrosine kinase domain using the crystal structures PDB 1M17 and PDB 4HJO with Erlotinib serving as the reference inhibitor. The docking investigations displayed that some derivatives had a high binding affinity within the EGFR's ATP-binding region. Compound 1e had the greatest binding affinity, with docking scores of -9.5 kcal/mol (1M17) and -11.9 kcal/mol (4HJO), outperforming the conventional medication in the inactive EGFR configuration. Interaction analysis indicated the formation of hydrogen bonding, π–π stacking, and hydrophobic interactions with key residues such as LYS721, MET742, VAL702 and LEU820, contributing to the stability of the ligand–protein complex. The designed hybrids were further assessed for their pharmacokinetic properties using in-silico ADMET prediction. Most derivatives complied with Lipinski's Rule of Five and Veber's Rule indicating good drug-likeness and oral bioavailability. Furthermore, compounds 1e and 1f have good pharmacokinetic characteristics, moderate solubility, adequate absorption, and non-mutagenic toxicity profiles.
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