•  
  •  
 

Indonesian Journal of Medical Chemistry and Bioinformatics

Abstract

Thyroid peroxidase (TPO) is a crucial enzyme in the biosynthesis of thyroid hormones, catalyzing the iodination of tyrosine residues in thyroglobulin and the coupling of iodotyrosines to form thyroxine (T4) and triiodothyronine (T3). Propylthiouracil (PTU) is an antithyroid drug commonly used to manage hyperthyroidism by inhibiting TPO. Understanding the molecular interactions between TPO and PTU can provide insights into the inhibitory mechanisms and guide the design of more effective antithyroid medications. Objective: This study aims to elucidate the binding interactions between TPO and PTU through molecular docking, providing a detailed understanding of how PTU inhibits TPO activity. Methods: The three-dimensional structure of TPO was obtained from Prosite and modelling by swissmodel and prepared for docking. The structure of PTU was optimized, and molecular docking was performed using AutoDock. The binding affinity, binding poses, and key interactions between TPO and PTU were analyzed. Visualization of the docking results was performed using PyMOL to identify critical residues involved in PTU binding. Results: The docking analysis revealed that PTU binds effectively to the active site of TPO with a binding affinity of -5.45 kcal/mol. The interaction involves coordination with the heme group and several key residues, including His239, which coordinates the heme, and Ser314, which forms hydrogen bonds with PTU. Additionally, hydrophobic interactions with residues Phe241 and Ile399 stabilize the binding of PTU in the active site. Conclusion: The docking study highlights the significant interactions between PTU and TPO, elucidating the molecular basis of TPO inhibition by PTU. The binding affinity and key interactions identified in this study provide a foundation for the design of more potent antithyroid drugs.

Bahasa Abstract

Tiroid peroksidase (TPO) adalah enzim penting dalam biosintesis hormon tiroid, mengkatalisis iodinasi residu tirosin dalam tiroglobulin dan penggabungan iodotirosin untuk membentuk tiroksin (T4) dan triiodothyronine (T3). Propylthiouracil (PTU) adalah obat antitiroid yang biasa digunakan untuk mengatasi hipertiroidisme dengan menghambat TPO. Memahami interaksi molekuler antara TPO dan PTU dapat memberikan wawasan tentang mekanisme penghambatan dan desain obat antitiroid yang lebih efektif. Penelitian ini bertujuan untuk menjelaskan interaksi pengikatan antara TPO dan PTU melalui molekuler docking, memberikan pemahaman rinci tentang bagaimana PTU menghambat aktivitas TPO. Metode : Struktur tiga dimensi TPO diperoleh dari Prosite dan dimodelkan oleh swissmodel dan disiapkan untuk docking. Struktur PTU dioptimalisasi, dan docking molekuler dilakukan menggunakan AutoDock. Afinitas pengikatan, binding poses, dan interaksi utama antara TPO dan PTU dianalisis. Visualisasi hasil docking dilakukan menggunakan PyMOL untuk mengidentifikasi residu penting yang terlibat dalam pengikatan PTU. Hasil : Analisis docking menunjukkan bahwa PTU berikatan efektif dengan situs aktif TPO dengan afinitas pengikatan -5,45 kcal/mol. Interaksi tersebut melibatkan koordinasi dengan gugus heme dan beberapa residu utama, termasuk His239, yang mengoordinasikan heme, dan Ser314, yang membentuk ikatan hidrogen dengan PTU. Selain itu, interaksi hidrofobik dengan residu Phe241 dan Ile399 menstabilkan pengikatan PTU di situs aktif. Kesimpulan : Studi docking menyoroti interaksi signifikan antara PTU dan TPO, menjelaskan dasar molekuler penghambatan TPO oleh PTU. Afinitas pengikatan dan interaksi kunci yang diidentifikasi dalam penelitian ini memberikan landasan untuk desain obat antitiroid yang lebih manjur.

References

  1. Regard, J.B.; Harrison, T.J.; Axford, J.; Axford, L.; Lee, L.; Ren, X.; et. al. Discovery of a novel, highly potent and orally bioavailable pyrrolidinone indole series of irreversible myeloperoxidase (MPO) inhibitors. Social Science Research Network, 2023, 115418- 1154. doi: 10.2139/ssrn.4198908
  2. Habza-Kowalska, E.; Kaczor, A.A.; Zuk, J.; Matosiuk, D.; Gawlik-Dziki, E. Thyroid peroxidase activity is inhibited by phenolic compounds-impact of interaction. Molecules, 2019, 24(15):2766-. doi: 10.3390/MOLECULES24152766
  3. Habza-Kowalska, E.; Gawlik-Dziki, U.; Dziki, D. Mechanism of action and interactions between thyroid peroxidase and lipoxygenase inhibitors derived from plant sources, Biomolecules, 2019, 9(11):663-. doi: 10.3390/BIOM9110663
  4. Pradhan, S.; Sarma, H.; Bharadwaz, B.; Mattaparthi, V.S.K. 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, 2017, 7(1):1-9. doi: 10.4172/2155-9937.1000131
  5. Sirohi, H.V.; Singh, P.K.; Iqbal, N.; Sharma, P.; Singh, A.K.; Kaur, P.; et.al. Design of anti-thyroid drugs: Binding studies and structure determination of the complex of lactoperoxidase with 2-mercaptoimidazole at 2.30 Å resolution. Proteins, 2017, 85(10):1882-1890. doi: 10.1002/PROT.25342
  6. Hosseinzadeh, B.; Beni, A.S.; Eskandari, R.; Karami, M.; Khorram, M. Interaction of propylthiouracil, an anti-thyroid drug with boron nitride nanotube: a DFT study. Adsorption-journal of The International Adsorption Society, 2020, 26(8):1385-1396. doi: 10.1007/S10450-020-00248-X
  7. Gupta, M.K.; Misra, K. Modeling and simulation analysis of propyl-thiouracil (PTU), an anti-thyroid drug on thyroid peroxidase (TPO), thyroid stimulating hormone receptor (TSHR), and sodium iodide (NIS) symporter based on systems biology approach. Network Modeling Analysis in Health Informatics and BioInformatics, 2013, 2(1):45-57. doi: 10.1007/S13721-013-0023-0
  8. Roy, G.; Mugesh, G. Bioinorganic chemistry in thyroid gland: effect of antithyroid drugs on peroxidase-catalyzed oxidation and iodination reactions. Bioinorganic Chemistry and Applications, 2006, 2006:23214-23214. doi: 10.1155/BCA/2006/23214
  9. Taurog, A.; Dorris, M.L. A reexamination of the proposed inactivation of thyroid peroxidase in the rat thyroid by propylthiouracil. Endocrinology, 1989, 124(6):3038-3042. doi: 10.1210/ENDO-124-6-3038
  10. Ruf, J.; Carayon, P. Structural and functional aspects of thyroid peroxidase . Archives of Biochemistry and Biophysics, 2006, 445 (2): 269–77. doi:10.1016/j.abb.2005.06.023
  11. 11. Kimura, S.; Kotani, T.; McBride, O.W.; Umeki, K.; Hirai, K.; Nakayama, T.; Ohtaki, S. (Aug 1987). Human thyroid peroxidase: complete cDNA and protein sequence, chromosome mapping, and identification of two alternately spliced mRNAs. Proceedings of the National Academy of Sciences of the United States of America, 1987, 84 (16): 5555–9
  12. Kotani, T.; Umeki, K.; Yamamoto, I.; Takeuchi, M.; Takechi, S.; Nakayama, T.; Ohtaki, S. Nucleotide sequence of the cDNA encoding mouse thyroid peroxidase. Gene, 1993, 123(2): 289-90. doi: 10.1016/0378-1119(93)90141-o. PMID: 7916704.
  13. Drugs and Lactation Database (LactMed®) [Internet]. National Institute of Child Health and Human Development; Bethesda (MD): Dec 21, 2020. Propylthiouracil. [PubMed]
  14. Yoshihara, A.; Luo, Y.; Ishido, Y.; Usukura, K.; Oda,K.; Sue, M.; et al. Inhibitory effects of methimazole and propylthiouracil on iodotyrosine deiodinase 1 in thyrocytes. Endocr J, 2019, 66(4): 349-357. [PubMed]
  15. Sushmita, P.; Himakshi, Sarma, B.; Mattaparthi, V.S.K. 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, 2017, 7(1):1-9. doi: 10.4172/2155-9937.1000131
  16. Habza-Kowalska, E.; Kaczor, A.A.; Zuk, J.; Matosiuk, D.; Gawlik-Dziki, E. Thyroid peroxidase activity is inhibited by phenolic compounds—impact of interaction. Molecules, 2019, 24(15): 2766. https://doi.org/10.3390/molecules24152766
  17. Sunanda, P.; Kar, A.; Singh, M.; Singh, R.K.; Ganeshpurkar, A. Syringic acid, a novel thyroid hormone receptor-β agonist, ameliorates propylthiouracil-induced thyroid toxicity in rats. Journal of Biochemical and Molecular Toxicology, 2021, 35(8) doi: 10.1002/JBT.22814
  18. Awad, S.M.; Zohny, Y.M.; Ali, S.A.; Mahgoub, S.; Said, A.M. Design, synthesis, molecular modeling, and biological evaluation of novel thiouracil derivatives as potential antithyroid agents. Molecules, 2018, 23(11):2913-. doi: 10.3390/MOLECULES23112913

Download

Share

COinS