Exploring Potential EGFR Inhibitors from Isodon Serra Phytochemicals: Molecular Docking, Dynamics, and ADMET Analysis

ABSTRACT The human epidermal growth factor receptor (EGFR), a key oncogenic driver in various cancers, particularly non‐small cell lung cancer (NSCLC), was selected as the molecular target for this investigation. A validated molecular docking protocol was employed using AutoDock Vina, with re‐docking of the co‐crystallized ligand (PDB ID: 1M17) yielding an RMSD of 1.4095 Å, confirming reliability. A total of 155 phytochemicals from Isodon serra were screened based on binding affinity toward EGFR. From this dataset, ten compounds (40, 48, 57, 58, 59, 84, 88, 89, 119, and 146) were identified as top candidates according to their strong binding energies (≤ −9.0 kcal/mol), all exceeding that of the reference inhibitor erlotinib (−7.18 kcal/mol). These top compounds formed key interactions with EGFR catalytic residues, mirroring the binding profile of erlotinib. Compound 88 (11,12‐epoxy‐2,3,13‐trihydroxy‐γ‐lactone oleanan‐28‐oic acid) showed the highest binding affinity (−10.42 kcal/mol). Molecular dynamics (MD) simulations over 100 ns confirmed the structural stability of these ligand–EGFR complexes. RMSD, RMSF, and radius of gyration (Rg) analyses revealed that complexes particularly stabilized the EGFR protein, maintaining compact conformations and reduced residue fluctuations compared to apo and reference systems. ADMET profiling indicated generally favorable pharmacokinetic properties, although limitations related to solubility and potential toxicity were identified for several studied compounds. DFT calculations supported the electronic stability and reactivity of the top ligands, with compound 88 displaying a favorable electronic profile. Collectively, this integrated in silico approach highlights Isodon serra phytochemicals, especially compound 88, as promising natural EGFR inhibitors. These findings provide a rational basis for subsequent experimental validation (in vitro and in vivo) and the development of novel anticancer agents targeting EGFR.