Biyoaktif Bileşiklerden Yararlanma: Östrojen Reseptörüyle İlişkili Patolojilerde Hesperidin ve Türevleri

Öz

Amaç: Hesperidin ve türevleri olan hesperetin, diosmin, diosmetin ve neohesperidin, ağırlıklı olarak narenciye meyvelerinde bulunan biyoaktif bileşiklerdir. Bu bileşikler, özellikle östrojen reseptörüyle ilişkili hastalıklardaki potansiyel terapötik etkileri nedeniyle önemli ölçüde ilgi görmektedir. Bu çalışma, hesperidin ve türevlerinin östrojen reseptör alfa (ER-α) ile olan bağlanma afinitelerini ve etkileşim mekanizmalarını moleküler docking (bağlanma simülasyonu) teknikleri kullanarak değerlendirmeyi amaçlamaktadır. Yöntemler: Hesperidin türevlerinin ER-α ile bağlanma enerjilerini belirlemek amacıyla moleküler docking simülasyonları gerçekleştirilmiştir. Ayrıca, biyoyararlanım, kan-beyin bariyeri geçirgenliği ve bağırsak emilimi gibi farmakokinetik özellikleri değerlendirmek için ADMET (Emilim, Dağılım, Metabolizma, Atılım ve Toksisite) analizi yapılmıştır. Bulgular: Diosmin, türevler arasında en yüksek bağlanma afinitesini göstermiş ve bu değeriyle standart bir anti-kanser ilacı olan Tamoksifen’e yakın bir bağlanma enerjisi elde etmiştir. Ancak, biraz daha düşük bağlanma enerjisi klinik etkinliğini etkileyebilir. Neohesperidin umut verici bir bağlanma afinitesi göstermiştir, ancak zayıf bağırsak emilimi nedeniyle biyoyararlanımı sınırlıdır. ADMET analizi, bu flavonoidlerin genel olarak olumlu farmakokinetik özelliklere sahip olduğunu, ancak zayıf kan-beyin bariyeri geçirgenliği ve değişken emilim oranları gibi bazı etkenlerin terapötik etkinliklerini sınırlayabileceğini ortaya koymuştur. Sonuç: Belirli farmakokinetik zorluklara rağmen, hesperidin ve türevleri ER-α ile umut verici etkileşimler sergilemekte olup, Tamoksifen'e alternatif veya tamamlayıcı tedavi seçenekleri olarak potansiyele sahiptir.

Anahtar Kelimeler

• Hesperidin
• Diosmin
• Östrojen Reseptörü
• Moleküler Docking
• Farmakokinetik
• Biyoyararlanım

Harnessing Bioactive Compounds: Hesperidin and Its Derivatives in Estrogen Receptor-Related Pathologies

Öz

Aim: Hesperidin and its derivatives, including hesperetin, diosmin, diosmetin, and neohesperidin, are flavonoids predominantly found in citrus fruits. These compounds have gained significant interest due to their potential therapeutic effects, particularly in estrogen receptorrelated diseases. This study aims to evaluate the binding affinities and interaction mechanisms of hesperidin and its derivatives with estrogen receptor alpha (ER-α) using molecular docking techniques. Methods: Molecular docking simulations were performed to determine the binding energies of hesperidin derivatives with ER-α. ADMET (Absorption, Distribution, Metabolism, Excretion, and Toxicity) analysis was conducted to evaluate pharmacokinetic properties, including bioavailability, blood-brain barrier permeability, and intestinal absorption. Results: Diosmin exhibited the highest binding affinity among the derivatives, with a binding energy comparable to Tamoxifen, a standard anti-cancer drug. However, its slightly lower binding energy may affect its clinical efficacy. Neohesperidin demonstrated promising affinity but had poor intestinal absorption, limiting its bioavailability. ADMET analysis revealed that while these flavonoids generally have favorable pharmacokinetic properties, factors such as poor blood-brain barrier permeability and variable absorption rates may restrict their therapeutic effectiveness. Conclusion: Despite certain pharmacokinetic challenges, hesperidin and its derivatives exhibit promising interactions with ER-α, suggesting their potential as alternative or adjunct therapies to Tamoxifen.

Anahtar Kelimeler

• Hesperidin
• Diosmin
• Estrogen Receptor
• Molecular Docking
• Pharmacokinetics
• Bioavailability

Kaynakça

1. 1. Pyrzynska K. Hesperidin: A Review on Extraction Methods, Stability and Biological Activities. Nutrients 2022;14(12):2387. Available from: https://doi.org/10.3390/nu14122387
2. 2. Choi S-S, Lee S-H, Lee K-A. A Comparative Study of Hesperetin, Hesperidin and Hesperidin Glucoside: Antioxidant, Anti-Inflammatory, and Antibacterial Activities In Vitro. Antioxidants 2022;11(8):1618. Available from: https://doi.org/10.3390/antiox11081618
3. 3. Borghi SM, Pavanelli WR. Antioxidant Compounds and Health Benefits of Citrus Fruits. Antioxidants 2023;12(8):1526. Available from: https://doi.org/10.3390/antiox12081526
4. 4. Ortiz AdC, et al. Therapeutic Effects of Citrus Flavonoids Neohesperidin, Hesperidin and Its Aglycone, Hesperetin on Bone Health. Biomolecules 2022;12(5):626. Available from: https://doi.org/10.3390/biom12050626
5. 5. Khorasanian AS, et al. The effects of hesperidin supplementation on cardiovascular risk factors in adults: A systematic review and dose–response meta analysis. Frontiersin Nutrition 2023;10:1177708. Available from: https://doi.org/10.3389/fnut.2023.1177708
6. 6. Hu H-Y, et al. Hesperidin Anti-Osteoporosis by Regulating Estrogen Signaling Pathways. Molecules 2023;28(19):6987. Available from: https://doi.org/10.3390/molecules28196987
7. 7. Safe S, et al. Flavonoids: structure–function and mechanisms of action and opportunities for drug development. Toxicol Res 2021; 37:147–162. Available from: https://doi.org/10.1007/s43188-020-00080-z
8. 8. Berman HM, et al. The Protein Data Bank. Nucleic Acids Res 2000;28(1):235-42. Available from: https://doi.org/10.1093/nar/28.1.235

9. 9. Shiau AK, et al. The structural basis of estrogen receptor/coactivator recognition and the antagonism of this interaction by tamoxifen. Cell. 1998; 95(7):927-37. Available from: https://doi.org/10.1016/s0092-8674(00)81717-1.
10. 10. BIOVIA DS, Dassault Systèmes, Discovery Studio. San Diego, CA, USA: Accelrys Inc; 2017
11. 11. Morris GM, et al. AutoDock4 and AutoDockTools4: Automated docking with selective receptor flexibility. J Comput Chem. 2009; 30(16):2785-91. Available from: https://doi.org/10.1002/jcc.21256
12. 12. Pires DE, Blundell TL, Ascher DB. pkCSM: Predicting Small-Molecule Pharmacokinetic and Toxicity Properties Using Graph-Based Signatures. J Med Chem 2015; 58(9):4066-72. Available from: https://doi.org/10.1021/acs.jmedchem.5b00104
13. 13. Madureira MB, et al. Naringenin and Hesperidin as Promising Alternatives for Prevention and Co-Adjuvant Therapy for Breast Cancer. Antioxidants 2023;12(3):586. Available from: https://doi.org/10.3390/antiox12030586
14. 14. Khamis AA, Ali EMM, Salim EI. Synergistic effects of bee venom, hesperidin, and piperine with tamoxifen on apoptotic and angiogenesis biomarker molecules against xerographic MCF-7 injected rats. Sci Rep 2024;14:1510. Available from: https://doi.org/10.1038/s41598-023-50729-6
15. 15. Zhang, Q., et al. Antiosteoporotic effect of hesperidin against ovariectomy-induced osteoporosis in rats via reduction of oxidative stress and inflammation. Journal of Biochemical and Molecular Toxicology, 2021; 35(8):e22832. Available from: https://doi.org/10.1002/jbt.22832
16. 16. Liu XM, et al. Dietary total flavonoids intake and risk of mortality from all causes and cardiovascular disease in the general population: a systematic review and meta-analysis of cohort studies. Mol Nutr Food Res 2017;61(6); 1601003 Available from: https://doi.org/10.1002/mnfr.201601003
17. 17. Xia N, et al. Synthesis of Hydrophobic Propionyl Neohesperidin Ester Using an Immobilied Enzyme and Description of Its Anti-proliferative and Pro-apoptotic Effects on MCF-7 Human Breast Cancer Cells. Frontiers in Bioengineering and Biotechnology 2020 8:544714. Available from: https://doi.org/10.3389/fbioe.2020.01025
18. 18. Abdullahi SH, Uzairu A, Shallangwa GA. In-silico activity prediction, structure-based drug design, molecular docking and pharmacokinetic studies of selected quinazoline derivatives for their antiproliferative activity against triple negative breast cancer (MDA-MB231) cell line. Bull Natl Res Cent 2022; 46:2. Available from: https://doi.org/10.1186/s42269-021-00690-z
19. 19. Evans JA, Mendonca P, Soliman KFA. Neuroprotective Effects and Therapeutic Potential of the Citrus Flavonoid Hesperetin in Neurodegenerative Diseases. Nutrients 2022;14(11):2228. Available from: https://doi.org/10.3390/nu14112228