Radioiodinated Anastrozole and Epirubicin for HER2-Targeted Cancer Therapy: Molecular Docking and Dynamics Insights with Implications for Nuclear Imaging

Abstract

This study evaluates radioiodinated anastrozole ([125I]anastrozole) and epirubicin ([125I]epirubicin) for HER2-targeted cancer therapy, utilizing radiopharmaceutical therapy (RPT) for personalized treatment of HER2-positive cancers. Through molecular docking and dynamics simulations (200 ns), it investigates these compounds’ binding affinities and mechanisms to the HER2 receptor compared to lapatinib, a known HER2 inhibitor. Molecular docking studies identified [125I]epirubicin with the highest ΔGbind (−10.92 kcal/mol) compared to lapatinib (−10.65 kcal/mol) and [125I]anastrozole (−9.65 kcal/mol). However, these differences were not statistically significant. Further molecular dynamics (MD) simulations are required to better understand the implications of these findings on the therapeutic potential of the compounds. MD simulations affirmed a stable interaction with the HER2 receptor, indicated by an average RMSD of 4.51 Å for [125I]epirubicin. RMSF analysis pointed to significant flexibility at key receptor regions, enhancing the inhibitory action against HER2. The [125I]epirubicin complex maintained an average of four H-bonds, indicating strong and stable interactions. The average Rg values for [125I]anastrozole and [125I]epirubicin complexes suggest a modest increase in structural flexibility without compromising protein compactness, reflecting their potential to induce necessary conformational changes in the HER2 receptor function. These analyses reveal enhanced flexibility and specific receptor region interactions, suggesting adaptability in binding, which could augment the inhibitory action against HER2. MM-PBSA calculations indicate the potential of these radioiodinated compounds as HER2 inhibitors. Notably, [125I]epirubicin exhibited a free binding energy of −65.81 ± 0.12 kJ/mol, which is comparable to lapatinib at −64.05 ± 0.11 kJ/mol and more favorable than [125I]anastrozole at −57.18 ± 0.12 kJ/mol. The results suggest electrostatic interactions as a major contributor to the binding affinity. The computational analysis underscores that [125I]anastrozole and [125I]epirubicin may have a promising role as HER2 inhibitors, especially [125I]epirubicin due to its high binding affinity and dynamic receptor interactions. These findings, supported by molecular docking scores and MM-PBSA binding energies, advocate for their potential superior inhibitory capability against the HER2 receptor. To validate these computational predictions and evaluate the therapeutic potential of these compounds for HER2-targeted cancer therapy, it is essential to conduct empirical validation through both in vitro and in vivo studies.