Computational insights into 131I-labeled hesperidin as a multi-target breast cancer therapeutic

Context: Breast cancer remains the second leading cause of cancer-related mortality worldwide, driven by uncontrolled cellular proliferation and metastasis. Natural radiopharmaceuticals have gained interest due to their potential for reduced side effects compared to synthetic agents. Among these, hesperidin and hesperetin, especially in iodinated forms, have emerged as promising therapeutic candidates targeting key breast cancer-related signaling pathways. Aims: To evaluate iodinated hesperidin derivatives as multi-target breast cancer therapeutics using molecular docking (AutoDock) and dynamics (GROMACS). Methods: Multi-target molecular docking and 100 ns molecular dynamics simulations were conducted to examine interactions with key breast cancer proteins: EGFR kinase, human estrogen receptor alpha (ER-α), and I-kappa-B-alpha/NF-kappa-B. Binding energies (∆G) were computed, and complex stability was assessed using RMSD, RMSF, and MM-PBSA analyses. Pharmacokinetic and toxicity properties were also predicted. Results: Docking results indicated strong affinities for iodinated derivatives (-6.14 to -7.51 kcal/mol), notably with EGFR and ER-α. Molecular dynamics simulations confirmed enhanced stability and reduced structural fluctuations in iodinated complexes. MM-PBSA calculations showed improved binding free energies, supporting increased interaction strength. Despite lower solubility, ADME predictions suggested favorable gastrointestinal absorption and drug-likeness for iodinated hesperetin. Toxicity analyses predicted moderate nephrotoxicity and cardiotoxicity risks, with lower LD50 values, indicating a need for dose optimization. Conclusions: Iodinated hesperidin and hesperetin exhibit stable binding interactions and favorable pharmacological profiles, highlighting their potential as novel radiopharmaceuticals in breast cancer therapy. These findings warrant further preclinical investigation and optimization for future drug development.