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Moleküler Modelleme Yoluyla Levotiroksinin AFP ile Kararlı Bir Etkileşiminin Araştırılması

Year 2025, Volume: 46 Issue: 2, 274 - 285, 30.06.2025

Emel Akbaba , Deniz Karataş , Ataman Gönel , Ezgi Soylu , Beste Kiraz , Yusur Ammar Almahdi

https://doi.org/10.17776/csj.1599148

Abstract

Tiroid disfonksiyonları tüm dünyada yaygındır ve buna bağlı olarak tiroid ilaçlarının kullanımı artmıştır. Tümör belirteçlerinin yanlış ölçülmesi kanser vakalarının gözden kaçmasına yol açabilir. En çok kullanılan kanser belirteçleri CA19-9, CA125, CEA, PSA ve AFP molekülleridir. Bu çalışmada, bu belirteçlerin tiroid ilaçları olan levotiroksin, metimazol ve propiltiyourasil ile moleküler etkileşimleri moleküler yerleştirme ve dinamik simülasyonları yoluyla araştırılmıştır. Moleküler yerleştirme çalışmalarında, levotiroksinin düşük konsantrasyonlarda AFP, CEA ve CA15-3 ile etkileşime girdiği gösterilmiştir. MD simülasyonları sonucunda, AFP/LEVO modeli en yüksek etkileşim seviyesini göstermiştir. Örneğin, AFP/Levotiroksin kompleksinin RMSD değerleri sürekli olarak 0,7 civarındayken, diğerleri için 1'in üzerinde gözlendi. Bu sıkı bağlanma etkileşim enerjilerine yansıdı ve AFP/Levotiroksin modelindeki toplam etkileşim -192,04 kJ/mol olarak hesaplandı. Buna karşılık, CA15-3/Levotiroksin ve CEA/Levotiroksin kompleksleri için bu değerler sırasıyla -135,26 ve -88,56 kJ/mol olarak hesaplandı. SASA analizi ayrıca, ligand maskelemesi ve standart sapmadaki azalma nedeniyle AFP/Levotiroksin kompleksinin üstünlüğünü de önerdi, çünkü SASA ortalama fark alanı -0,46 olarak bulundu.

Keywords

Levotiroksin AFP CEA CA 15-3 moleküler modelleme

References

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  • [8] Seale K.N., Tkaczuk K.H.R., Circulating Biomarkers in Breast Cancer, Clin Breast Cancer, 22(3) (2022) e319-e331.
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  • [20] Lu Y., Molecular Dynamic Simulation To Reveal the Mechanism Underlying MGL-3196 Resistance to Thyroxine Receptor Beta, ACS Omega, 9(19) (2024) 20957-20965.
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  • [31] Tang S., Sun L., Wang F., Identification of highly active natural thyroid hormone receptor agonists by pharmacophore-based virtual screening, J. Biomol. Struct. Dyn., 39(3) (2021) 901-910.
  • [32] Bagci E., Evaluation of antiamnesic activity of Salvia multicaulis essential oil on scopolamine-induced amnesia in rats: in vivo and in silico approaches, Heliyon, 5(8) (2019) e02223.
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  • [38] Rampogu S., Molecular Docking and Molecular Dynamics Simulations Discover Curcumin Analogue as a Plausible Dual Inhibitor for SARS-CoV-2, International Journal of Molecular Sciences, 23(3) (2022).
  • [39] Shoaib T.H., Exploring the potential of approved drugs for triple-negative breast cancer treatment by targeting casein kinase 2: Insights from computational studies, Plos One. 18(8) (2023).
  • [40] Zhang D., Lazim R., Application of conventional molecular dynamics simulation in evaluating the stability of apomyoglobin in urea solution, Sci Rep., 7(2017) 44651.
  • [41] Johnson K.J., Cygan R.T., Fein J.B., Molecular simulations of metal adsorption to bacterial surfaces, Geochimica Et Cosmochimica Acta., 70(20) (2006) 5075-5088.

Investigation of a Stable Interaction of Levothyroxine with AFP Through Molecular Modelling

Year 2025, Volume: 46 Issue: 2, 274 - 285, 30.06.2025

Emel Akbaba , Deniz Karataş , Ataman Gönel , Ezgi Soylu , Beste Kiraz , Yusur Ammar Almahdi

https://doi.org/10.17776/csj.1599148

Abstract

Thyroid dysfunctions are common all over the world, and accordingly, the use of thyroid drugs has increased. Incorrect measurement of tumor markers may lead to missed cases of cancer. The most used cancer markers are CA19-9, CA125, CEA, PSA, and AFP molecules. In this study, the molecular interactions of these markers with the thyroid medications of levothyroxine, methimazole, and propylthiouracil were investigated via molecular docking and dynamics simulations. In the molecular docking studies, levothyroxine was shown to interact with AFP, CEA, and CA15-3 in low concentrations. As a result of the MD simulations, the AFP/LEVO model exhibited the highest level of interaction. For instance, while the RMSD values of AFP/Levothyroxine complex were consistently around 0.7, and for the others they were observed above 1. This tight binding was reflected in interaction energies, with the total interaction in the AFP/Levothyroxine model computed as -192.04 kJ/mol. In contrast, for CA15-3/Levothyroxine and CEA/Levothyroxine complexes, these values were calculated as -135.26 and -88.56 kJ/mol, respectively. The SASA analysis also suggested the superiority of AFP/Levothyroxine complex due to ligand masking and a decrease in standard deviation, as the SASA mean difference area was found to be -0.46.

Keywords

Levothyroxine AFP CEA CA 15-3 molecular modelling

References

  • [1] Taylor P.N., Global epidemiology of hyperthyroidism and hypothyroidism, Nat. Rev. Endocrinol., 14(5) (2018) 301-316.
  • [2] Chiovato L., Magri F., Carlé A., Hypothyroidism in Context: Where We’ve Been and Where We’re Going, Advances in Therapy, 36(S2) (2019) 47-58.
  • [3] Hughes K., Eastman C., Thyroid disease: Long-term management of hyperthyroidism and hypothyroidism, Aust. J. Gen. Pract., 50(1-2) (2021) 36-42.
  • [4] Guerri G., Hypothyroidism and hyperthyroidism, Acta Biomed., 90(10-S) (2019) 83-86.
  • [5] Kravets I., Hyperthyroidism: Diagnosis and Treatment, Am. Fam. Physician., 93(5) (2016) 363-70.
  • [6] Silsirivanit A., Glycosylation Markers in Cancer, Adv. Clin. Chem., 89(2019) 189-213.
  • [7] Lee T., Teng T.Z.J., Shelat V.G., Carbohydrate antigen 19-9 - tumor marker: Past, present, and future, World J. Gastrointest Surg., 12(12) (2020) 468-490.
  • [8] Seale K.N., Tkaczuk K.H.R., Circulating Biomarkers in Breast Cancer, Clin Breast Cancer, 22(3) (2022) e319-e331.
  • [9] Zhang M., Roles of CA125 in diagnosis, prediction, and oncogenesis of ovarian cancer, Biochim. Biophys. Acta. Rev. Cancer, 1875(2) (2021) 188503.
  • [10] Zheng Y., Zhu M., Li M., Effects of alpha-fetoprotein on the occurrence and progression of hepatocellular carcinoma, J. Cancer Res. Clin. Oncol., 146(10) (2020) 2439-2446.
  • [11] Carlsson S.V., Vickers A.J., Screening for Prostate Cancer, Med. Clin. North Am., 104(6) (2020) 1051-1062.
  • [12] Torres P.H.M., Key Topics in Molecular Docking for Drug Design, Int. J. Mol. Sci., 20(18) (2019).
  • [13] Pinzi L., Rastelli G., Molecular Docking: Shifting Paradigms in Drug Discovery, Int. J. Mol. Sci., 20(18) (2019).
  • [14] Akbaba E., Improvement of memory deficits via acetylcholinesterase inhibitory activity of Nepeta nuda ssp. nuda essential oil in rats, Kuwait Journal of Science, 48(3) (2021).
  • [15] Fu H., Accurate determination of protein:ligand standard binding free energies from molecular dynamics simulations, Nat Protoc., 17(4) (2022) 1114-1141.
  • [16] Li J., Fu A., Zhang L., An Overview of Scoring Functions Used for Protein-Ligand Interactions in Molecular Docking, Interdiscip Sci., 11(2) (2019) 320-328.
  • [17] Hollingsworth S.A., Dror R.O., Molecular Dynamics Simulation for All, Neuron, 99(6) (2018) 1129-1143.
  • [18] Suryandari D.A., Molecular Insights into Propylthiouracil as a Thyroid Peroxidase Inhibitor: A Computational Study Approach, Indonesian Journal of Medical Chemistry and Bioinformatics. 3(1) (2024).
  • [19] Li H., Integrated computational analysis of molecular mechanisms underlying perfluorooctane sulfonic acid induced thyroid toxicity, Sci Rep., 15(1) (2025) 7920.
  • [20] Lu Y., Molecular Dynamic Simulation To Reveal the Mechanism Underlying MGL-3196 Resistance to Thyroxine Receptor Beta, ACS Omega, 9(19) (2024) 20957-20965.
  • [21] Pradhan S., Comparative Study on the Binding Affinity of Methimazole and Propylthiouracil to Thyroid Peroxidase as an Anti-Thyroid Drug: An Insilico Approach, Journal of Molecular Imaging & Dynamics, 07(01) (2017).
  • [22] Sandu N., Evaluation of the interaction of levothyroxine with bovine serum albumin using spectroscopic and molecular docking studies, J. Biomol. Struct. Dyn., 40(3) (2022) 1139-1151.
  • [23] Xiong D., Comprehensive Analysis Reveals That ISCA1 Is Correlated with Ferroptosis-Related Genes Across Cancers and Is a Biomarker in Thyroid Carcinoma, Genes (Basel), 15(12) (2024).
  • [24] Gulfidan G., Systems biomarkers for papillary thyroid cancer prognosis and treatment through multi-omics networks, Arch Biochem Biophys, 715(2022) 109085.
  • [25] Mahmud S., Gene-expression profile analysis to disclose diagnostics and therapeutics biomarkers for thyroid carcinoma, Comput Biol Chem., 113(2024) 108245.
  • [26] He Q., Combining Network Pharmacology with Molecular Docking for Mechanistic Research on Thyroid Dysfunction Caused by Polybrominated Diphenyl Ethers and Their Metabolites, Biomed. Res. Int., 2021(2021) 2961747.
  • [27] Shih M.L., Large-scale transcriptomic analysis of coding and non-coding pathological biomarkers, associated with the tumor immune microenvironment of thyroid cancer and potential target therapy exploration, Front Cell Dev. Biol., 10(2022) 923503.
  • [28] Morris G.M., AutoDock4 and AutoDockTools4: Automated docking with selective receptor flexibility, J. Comput. Chem., 30(16) (2009) 2785-91.
  • [29] O'Boyle, Open Babel: An open chemical toolbox, J. Cheminform, 3(2011) 33.
  • [30] Akbaba E., Karatas D., Phytochemicals of Hibiscus sabdariffa with Therapeutic Potential against SARS-CoV-2: A Molecular Docking Study, J. Inst. Sci. Technol., 13(2) (2023).
  • [31] Tang S., Sun L., Wang F., Identification of highly active natural thyroid hormone receptor agonists by pharmacophore-based virtual screening, J. Biomol. Struct. Dyn., 39(3) (2021) 901-910.
  • [32] Bagci E., Evaluation of antiamnesic activity of Salvia multicaulis essential oil on scopolamine-induced amnesia in rats: in vivo and in silico approaches, Heliyon, 5(8) (2019) e02223.
  • [33] Dedon J., Thyroid Disease in Aging, Mo. Med., 119(4) (2022) 351-353.
  • [34] Hirasawa M., Interaction of Nevirapine with the Peptide Binding Groove of HLA-DRB1*01:01 and Its Effect on the Conformation of HLA-Peptide Complex, Int. J. Mol. Sci. 19(6) (2018).
  • [35] Behera S.K., In Silico Analysis Determining the Binding Interactions of NAD(P)H: Quinone Oxidoreductase 1 and Resveratrol via Docking and Molecular Dynamic Simulations, Eur. J. Biol., 82(2) (2023) 280-288.
  • [36] Huang Y.H., CEACAM1 regulates TIM-3-mediated tolerance and exhaustion, Nature, 517(7534) (2015) 386-U566.
  • [37] Huang H.J., Lee C.C., Chen C.Y., Lead discovery for Alzheimer's disease related target protein RbAp48 from traditional Chinese medicine, Biomed. Res. Int., 2014(2014) 764946.
  • [38] Rampogu S., Molecular Docking and Molecular Dynamics Simulations Discover Curcumin Analogue as a Plausible Dual Inhibitor for SARS-CoV-2, International Journal of Molecular Sciences, 23(3) (2022).
  • [39] Shoaib T.H., Exploring the potential of approved drugs for triple-negative breast cancer treatment by targeting casein kinase 2: Insights from computational studies, Plos One. 18(8) (2023).
  • [40] Zhang D., Lazim R., Application of conventional molecular dynamics simulation in evaluating the stability of apomyoglobin in urea solution, Sci Rep., 7(2017) 44651.
  • [41] Johnson K.J., Cygan R.T., Fein J.B., Molecular simulations of metal adsorption to bacterial surfaces, Geochimica Et Cosmochimica Acta., 70(20) (2006) 5075-5088.
There are 41 citations in total.

Details

Primary Language English
Subjects Molecular Docking, Computational Chemistry, Bioengineering (Other)
Journal Section Natural Sciences
Authors

Emel Akbaba 0000-0003-4915-5153

Deniz Karataş 0000-0002-8176-4883

Ataman Gönel 0000-0001-7200-1537

Ezgi Soylu 0000-0003-1322-580X

Beste Kiraz 0009-0003-0125-8791

Yusur Ammar Almahdi 0009-0003-9569-3777

Publication Date June 30, 2025
Submission Date December 12, 2024
Acceptance Date May 19, 2025
Published in Issue Year 2025Volume: 46 Issue: 2

Cite

APA Akbaba, E., Karataş, D., Gönel, A., Soylu, E., et al. (2025). Investigation of a Stable Interaction of Levothyroxine with AFP Through Molecular Modelling. Cumhuriyet Science Journal, 46(2), 274-285. https://doi.org/10.17776/csj.1599148