Theoretical evaluation of technetium-to-rhenium substitution in hesperidin complexes for breast cancer theranostic potential

Hesperidin is a flavanone glycoside with antioxidant, anti-inflammatory, and anticancer activities, making it a potential ligand for breast cancer radiotheranostics. Because technetium and rhenium share coordination similarity, they can form matched diagnostic–therapeutic pairs using the same ligand scaffold. However, the electronic properties, binding stability, and dynamic interactions of technetium–hesperidin and rhenium–hesperidin complexes with breast cancer targets remain unclear. This study systematically evaluated their structural, electronic, and energetic profiles using an integrated in silico approach. Metal–hesperidin complexes were optimized, followed by DFT calculations (B3LYP; 6-31G(d); LANL2DZ). Docking was performed against ERα, HER2, AKT1, EGFR, and PIK3CA using AutoDock 4.2.3. Molecular dynamics simulations (100 ns) were conducted in GROMACS 2016.3 (AMBER99SB-ILDN), with ligand parameterization via ACPYPE. Stability and interactions were analyzed using RMSD, RMSF, Rg, SASA, RDF, and hydrogen bond occupancy. MM-PBSA binding energies were calculated using g_mmpbsa and MMPBSA.py. Both complexes reached stable minima without imaginary frequencies and showed similar HOMO–LUMO gaps (≈0.087–0.088 Hartree). Molecular docking predicted favorable binding of both complexes toward breast cancer–related targets, whereas MM-PBSA analysis revealed receptor-dependent energetic preferences. Technetium–hesperidin exhibited the most favorable binding free energy for AKT1 (−282.810 ± 52.209 kJ/mol), while rhenium–hesperidin showed a more favorable mean binding free energy toward EGFR (−47.729 ± 53.604 kJ/mol), although the relatively large variability observed for the EGFR system warrants cautious interpretation. These findings indicate that molecular docking and MM-PBSA provide complementary insights into ligand–receptor interactions and support the potential of hesperidin as a promising scaffold for receptor-dependent technetium/rhenium radiotheranostic design, warranting further experimental validation.