J. Pharm. Pharmacogn. Res., vol. 13, Supplement 1, pp. S266-S288, Apr 2025.

DOI: https://doi.org/10.56499/jppres24.2295_13.s1.266

Original Article

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

[Perspectivas computacionales sobre la hesperidina marcada con ¹³¹I como terapia multidiana contra el cáncer de mama]

Taufik Muhammad Fakih^1,2, Dhania Novitasari^3,4, Mukh Syaifudin⁵, Edy Meiyanto⁶, Okid Parama Astirin⁷, Muthi’ Ikawati⁶, Muchtaridi Muchtaridi^3,4*

¹Doctoral Program of Pharmacy, Faculty of Pharmacy, Universitas Padjadjaran, Jl. Raya Bandung Sumedang, Sumedang, 45363, Indonesia.

²Department of Pharmacy, Faculty of Mathematics and Natural Sciences, Universitas Islam Bandung, Jl. Ranggagading, Bandung, 40116, Indonesia.

³Department of Pharmaceutical Analysis and Medicinal Chemistry, Faculty of Pharmacy, Universitas Padjadjaran, Jl. Raya Bandung Sumedang, Sumedang, 45363, Indonesia.

⁴Research Collaboration Centre for Theranostic Radiopharmaceuticals, National Research and Innovation Agency (BRIN), Jl. Raya Bandung Sumedang, Sumedang, 45363, Indonesia.

⁵Research Center for Radioisotope, Radiopharmaceutical and Biodosimetry Technology, Research Organization for Nuclear Energy, National Research and Innovation Agency (BRIN), Jl. Raya Puspiptek, Tangerang Selatan, 15314, Indonesia.

⁶Laboratory of Macromolecular Engineering, Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Universitas Gadjah Mada, Jl. Sekip Utara, Yogyakarta, 55281, Indonesia.

⁷Department of Biology, Faculty of Mathematics and Natural Science, Universitas Sebelas Maret, Jl. Ir. Sutami, Surakarta 57126, Indonesia.

*E-mail: muchtaridi@unpad.ac.id

Abstract

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.

Keywords: breast cancer; in silico approach; iodinated ligand; multi-targeted simulation; natural-based radiopharmaceutical.

Resumen

Contexto: El cáncer de mama sigue siendo la segunda causa principal de mortalidad por cáncer en todo el mundo, impulsado por la proliferación celular descontrolada y la metástasis. Los radiofármacos naturales han cobrado interés debido a su potencial para reducir los efectos secundarios en comparación con los agentes sintéticos. Entre estos, la hesperidina y la hesperetina, especialmente en formas yodadas, se han convertido en prometedores candidatos terapéuticos dirigidos a vías de señalización clave relacionadas con el cáncer de mama.

Objetivos: Evaluar los derivados yodados de hesperidina como terapias multidiana para el cáncer de mama mediante acoplamiento molecular (AutoDock) y dinámica molecular (GROMACS).

Métodos: Se realizaron simulaciones de acoplamiento molecular multidiana y dinámica molecular de 100 ns para examinar las interacciones con proteínas clave del cáncer de mama: quinasa del EGFR, receptor de estrógeno humano alfa (ER-α) e I-κB-α/NF-κB. Se calcularon las energías de enlace (∆G) y se evaluó la estabilidad del complejo mediante análisis de RMSD, RMSF y MM-PBSA. También se predijeron las propiedades farmacocinéticas y de toxicidad.

Resultados: Los resultados del acoplamiento indicaron fuertes afinidades por los derivados yodados (de -6,14 a -7,51 kcal/mol), en particular con EGFR y ER-α. Las simulaciones de dinámica molecular confirmaron una mayor estabilidad y una reducción de las fluctuaciones estructurales en los complejos yodados. Los cálculos de MM-PBSA mostraron una mejora de las energías libres de enlace, lo que respalda una mayor fuerza de interacción. A pesar de la menor solubilidad, las predicciones de ADME sugirieron una absorción gastrointestinal favorable y similitud farmacológica para la hesperetina yodada. Los análisis de toxicidad predijeron riesgos moderados de nefrotoxicidad y cardiotoxicidad, con valores de LD₅₀ más bajos, lo que indica la necesidad de optimizar la dosis.

Conclusiones: La hesperidina y la hesperetina yodadas presentan interacciones de unión estables y perfiles farmacológicos favorables, lo que destaca su potencial como nuevos radiofármacos en el tratamiento del cáncer de mama. Estos hallazgos justifican una mayor investigación preclínica y su optimización para el desarrollo futuro de fármacos.

Palabras Clave: cáncer de mama; enfoque in silico; ligando yodado; radiofármaco de origen natural; simulación multidiana.

 

https://jppres.com/jppres/pdf/vol13/jppres24.2295_13.s1.266.pdf

 

 

Citation Format: Fakih TM, Novitasari D, Syaifudin M, Meiyanto E, Astirin OP, Ikawati M, Muchtaridi M (2025) Computational insights into 131I-labeled hesperidin as a multi-target breast cancer therapeutic. J Pharm Pharmacogn Res 13(s1): S266–S288. https://doi.org/10.56499/jppres24.2295_13.s1.266

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