Electronic structure, topological characteristics and EGFR recognition of a novel imidazole derivative: an integrated DFT, molecular docking, dynamics and ADMET study

The molecular and electronic properties of 3-(4,5-diphenyl-1-(2-(piperazin-1-yl)ethyl)-1H-imidazol-2-yl)-1H-indole (DPEI) were investigated using density functional theory (DFT), topological analysis, molecular docking, molecular dynamics (MD), binding free-energy calculations, and ADMET prediction. The molecular geometry was optimised at the B3LYP/6-311++G(d,p) level to elucidate its electronic structure, charge distribution, donor-acceptor interactions, and non-covalent interactions. Molecular docking against the epidermal growth factor receptor (EGFR; PDB ID: 1M17) yielded a binding energy of −10.0 kcal mol−1 for DPEI, compared with −7.8 and −7.2 kcal mol−1 for gefitinib and erlotinib, respectively. A 100 ns MD simulation indicated sustained ligand accommodation within the binding pocket and overall complex stability. MM-PBSA and MM-GBSA calculations were performed to evaluate binding free energies and energetic contributions. DPEI exhibited favourable predicted physicochemical properties, including a molecular weight of 447.24 g mol−1, topological polar surface area of 48.88 Å2, logP of 3.704, and logD of 3.186, consistent with Lipinski's rule-of-five criteria. However, ADMET predictions indicated potential hERG inhibition, hepatotoxicity, mutagenicity, neurotoxicity, and respiratory toxicity. These findings identify DPEI as a promising computationally characterised EGFR-targeting scaffold requiring experimental validation of its biological activity, binding affinity, and safety.