Main Article Content

Abstract

Iron-overload can lead to organ damage by promoting free radical production.This study explores the potential inhibitory effects of compounds found in Phaleria macrocarpa fruit on non-transferrin-bound iron uptake by targeting DMT1 and ZIP14 iron transporters through in-silico methods.The study utilized homology modeling to construct 3D structures of DMT1 and ZIP14. Validation of these models was carried out by assessing their sequence identity and analyzing their stereochemical quality using Ramachandran plots. Molecular docking was conducted using AutoDockTools. The coordinates for molecular docking were carefully chosen based on the iron binding-site locations as reported in previous literature. Interaction visualization was done using LigPlot+. Our findings indicate strong binding affinities of several compounds from Phaleria macrocarpa fruit with both DMT1 and ZIP14. Specifically, patuletin-7-O-[6"-(2-methylbutyryl)]-glucoside, naringenin-4'-7-dimethyl ether, and 5,7,8,3',4'-pentamethoxyflavone demonstrated significant interaction with DMT-1, while 6'-O-galloyl-homoarbutin, patuletin-7-O-[6"-(2-methylbutyryl)]-glucoside, and guanine exhibited high affinity for ZIP14. While the ethanol extract of Phaleria macrocarpa fruit shows promising interactions with key iron transporters implicated in iron overload, these in-silico predictions require further experimental validation to confirm their efficacy as inhibitors.

Keywords

Molecular docking, Phaleria macrocarpa, DMT-1,ZIP-14, Iron overload

Article Details

How to Cite
1.
Rahma R, Estuningtyas A. Molecular Docking of Active Compounds from The Ethanol Extract of Phaleria macrocarpa Fruit with Iron Transporters DMT1 and ZIP14. EKSAKTA [Internet]. 2024Jun.30 [cited 2024Jul.13];25(02):231-46. Available from: https://eksakta.ppj.unp.ac.id/index.php/eksakta/article/view/508

References

  1. Zeidan, R.S., Martenson, M., Tamargo, J.A., McLaren, C., Ezzati, A., Lin, Y., et al. (2024). Iron homeostasis in older adults: balancing nutritional requirements and health risks. Journal of Nutrition, Health and Aging, 28 (5), 1–12.
  2. Katsarou, A. and Pantopoulos, K. (2020). Basics and principles of cellular and systemic iron homeostasis. Molecular Aspects of Medicine, 75 (May), 100866.
  3. dos Santos, L., Bertoli, S.R., Ávila, R.A., and Marques, V.B. (2022). Iron overload, oxidative stress and vascular dysfunction: Evidences from clinical studies and animal models. Biochimica et Biophysica Acta - General Subjects, 1866 (9), 1–12.
  4. Pan, L., Xie, Y., Yin, X., Huang, Y., Yang, G., Li, C., et al. (2023). Oxidative Stress Damage of Iron Overload on Bone Marrow Erythropoiesis, Heart and Liver in Non-Transfusion Dependent Thalassemia. Blood, 142 5245.
  5. Dhanya, R., Sedai, A., Ankita, K., Parmar, L., Agarwal, R.K., Hegde, S., et al. (2020). Life expectancy and risk factors for early death in patients with severe thalassemia syndromes in South India. Blood Advances, 4 (7), 1448–1457.
  6. Tantiworawit, A., Kamolsripat, T., Piriyakhuntorn, P., Rattanathammethee, T., Hantrakool, S., Chai-Adisaksopha, C., et al. (2024). Survival and causes of death in patients with alpha and beta-thalassemia in Northern Thailand. Annals of Medicine, 56 (1), 1–8.
  7. Ganz, T. and Nemeth, E. (2023). Pathogenic Mechanisms in Thalassemia II: Iron Overload. Hematology/Oncology Clinics of North America, 37 (2), 353–363.
  8. Koppenol, W.H. and Hider, R.H. (2019). Iron and redox cycling. Do’s and don’ts. Free Radical Biology and Medicine, 133 3–10.
  9. Knutson, M.D. (2019). Non-transferrin-bound iron transporters. Free Radical Biology and Medicine, 133 (August 2018), 101–111.
  10. Nakamura, T., Naguro, I., and Ichijo, H. (2019). Iron homeostasis and iron-regulated ROS in cell death, senescence and human diseases. Biochimica et Biophysica Acta - General Subjects, 1863 (9), 1398–1409.
  11. Chapchap, E.C., Silva, M.M.A., de Assis, R.A., Kerbauy, L.N., Diniz, M. da S., Rosemberg, L.A., et al. (2023). Cardiac iron overload evaluation in thalassaemic patients using T2* magnetic resonance imaging following chelation therapy: a multicentre cross-sectional study. Hematology, Transfusion and Cell Therapy, 45 (1), 7–15.
  12. Shindo, M., Torimoto, Y., Saito, H., Motomura, W., Ikuta, K., Sato, K., et al. (2006). Functional role of DMT1 in transferrin-independent iron uptake by human hepatocyte and hepatocellular carcinoma cell, HLF. Hepatology Research, 35 (3), 152–162.
  13. Jenkitkasemwong, S., Wang, C.Y., Coffey, R., Zhang, W., Chan, A., Biel, T., et al. (2015). SLC39A14 Is Required for the Development of Hepatocellular Iron Overload in Murine Models of Hereditary Hemochromatosis. Cell Metabolism, 22 (1), 138–150.
  14. Njeim, R., Naouss, B., Bou-Fakhredin, R., Haddad, A., and Taher, A. (2024). Unmet needs in β-thalassemia and the evolving treatment landscape. Transfusion Clinique et Biologique, 31 (1), 48–55.
  15. Chong, C.C., Redzuan, A.M., Sathar, J., and Makmor-Bakry, M. (2021). Patient Perspective on Iron Chelation Therapy: Barriers and Facilitators of Medication Adherence. Journal of Patient Experience, 8.
  16. Lindayana, Kusmardi, and Estuningtyas, A. (2022). The Effect of Ethanol Extract of Phaleria Macrocarpa Fruit in An Iron-Overloaded Rat Heart, Universitas Indonesia, 2022.
  17. Verna, F. Dela (2021). The hepatoprotective effect of mahkota dewa (Phaleria macrocarpa) fruit ethanol extract in iron-overload rats via iron chelating mechanism., University of Indonesia, 2021.
  18. Estuningtyas, A., Wahyuni, T., Wahidiyat, P.A., Poerwaningsih, E.H., and Freisleben, H.J. (2019). Mangiferin and mangiferin-containing leaf extract from Mangifera foetida L for therapeutic attenuation of experimentally induced iron overload in a rat model. Journal of HerbMed Pharmacology, 8 (1), 21–27.
  19. Asiamah, I., Obiri, S.A., Tamekloe, W., Armah, F.A., and Borquaye, L.S. (2023). Applications of molecular docking in natural products-based drug discovery. Scientific African, 20.
  20. Shah, M., Patel, M., Shah, M., Patel, M., and Prajapati, M. (2024). Computational transformation in drug discovery: A comprehensive study on molecular docking and quantitative structure activity relationship (QSAR). Intelligent Pharmacy, 2024.
  21. Manatschal, C., Pujol-Giménez, J., Poirier, M., Reymond, J.L., Hediger, M.A., and Dutzler, R. (2019). Mechanistic basis of the inhibition of slc11/nramp-mediated metal ion transport by bis-isothiourea substituted compounds. ELife, 8.
  22. Anantram, A., Janve, M., Degani, M., Singhal, R., and Kundaikar, H. (2018). Homology modelling of human divalent metal transporter (DMT): Molecular docking and dynamic simulations for duodenal iron transport. Journal of Molecular Graphics and Modelling, 85 145–152.
  23. Dawson, C.N. (2022). Disease-Causing Mutations in The Human Metal Ion Transporter ZIP14 Alter Its Structure, Ion Uptake Function and Trafficking, 2022.
  24. Hameduh, T., Haddad, Y., Adam, V., and Heger, Z. (2020). Homology modeling in the time of collective and artificial intelligence. Computational and Structural Biotechnology Journal, 18 3494–3506.
  25. Jisna, V.A. and Jayaraj, P.B. (2021). Protein Structure Prediction: Conventional and Deep Learning Perspectives. Protein Journal, 40 (4), 522–544.
  26. Chang, Y., Hawkins, B.A., Du, J.J., Groundwater, P.W., Hibbs, D.E., and Lai, F. (2023). A Guide to In Silico Drug Design. Pharmaceutics, 15 (49), 1–52.
  27. Singh, P., Shaikh, S., Gupta, S., and Gupta, R. (2023). In-silico development of multi-epitope subunit vaccine against lymphatic filariasis. Journal of Biomolecular Structure and Dynamics,.
  28. Mir, A., Song, Y., Lee, H., Khanahmad, H., Khorram, E., Nasiri, J., et al. (2023). Whole exome sequencing revealed variants in four genes underlying X-linked intellectual disability in four Iranian families: novel deleterious variants and clinical features with the review of literature. BMC Medical Genomics, 16 (239), 1–20.
  29. Li, T., Guo, R., Zong, Q., and Ling, G. (2022). Application of molecular docking in elaborating molecular mechanisms and interactions of supramolecular cyclodextrin. Carbohydrate Polymers, 276.
  30. García-Ortegón, M., Simm, G.N.C., Tripp, A.J., Hernández-Lobato, J.M., Bender, A., and Bacallado, S. (2022). DOCKSTRING: Easy Molecular Docking Yields Better Benchmarks for Ligand Design. Journal of Chemical Information and Modeling, 62 (15), 3486–3502.
  31. Ma, X., Pan, B., Wang, L., Feng, Z., and Peng, C. (2023). Network pharmacology and molecular docking elucidate potential mechanisms of Eucommia ulmoides in hepatic ischemia–reperfusion injury. Scientific Reports, 13 (20716), 1–14.
  32. Olugbogi, E.A., Arobadade, O.A., Bodun, D.S., Omoseeye, S.D., Omirin, E.S., Fapohunda, O., et al. (2023). Identification of apposite antagonist for androgen receptor in prostate cancer: an in silico study of fenugreek compounds. Journal of Biomolecular Structure and Dynamics.
  33. Madushanka, A., Moura, R.T., Verma, N., and Kraka, E. (2023). Quantum Mechanical Assessment of Protein–Ligand Hydrogen Bond Strength Patterns: Insights from Semiempirical Tight-Binding and Local Vibrational Mode Theory. International Journal of Molecular Sciences, 24 (7).
  34. Girdhar, N., Yadav, V., Kumari, N., Subbarao, N., and Krishnamachari, A. (2024). Insilico screening to identify novel inhibitors targeting 30S ribosomal protein S12 in meningitis-causing organism ‘Elizabethkingia meningoseptica.’ Journal of Biomolecular Structure and Dynamics.