In Silico Study of Brazilin from Secang Wood (Caesalpinia Sappan L) as a Candidate for Splenomegaly Therapy

Racy Youngest; Rusdianto Rusdianto; Yusof Kamisah; Ani Melani Maskoen; Ratu  Safitri

doi:10.31101/ijhst.v6i3.4032

Authors

Racy Youngest Universitas Padjadjaran, Indonesia
Rusdianto Rusdianto STIKes BTH, Indonesia
Yusof Kamisah Universiti Kebangsaan Malaysia, Malaysia
Ani Melani Maskoen Universitas Padjadjaran, Indonesia
Ratu Safitri Universitas Jenderal Achmad Yani, Indonesia

DOI:

https://doi.org/10.31101/ijhst.v6i3.4032

Keywords:

Caesalpinia sappan, in silico, JAK2 inhibitor, splenomegali, thalassemia

Abstract

Brazilin is a flavonoid found in secang (sappan) wood extract (Caesalpinia sappan L) currently undergoing clinical trials in phase 2 for the treatment of thalassemia patients. It is recognized for its antioxidant effects and its efficacy as a strong iron chelator, facilitating the binding and excretion of excess iron in the bloodstream of patients with thalassemia. This flavonoid compound may serve as a Janus kinase 2 (JAK2) inhibitor through the EPO/EPOR/JAK2/STAT5 pathway, which is responsible for splenomegaly (enlarged spleen). This study aims to investigate the mechanism by which sappan wood metabolite chemicals (brazilin) inhibit JAK2 in silico. This inhibition is expected to reduce splenomegaly in thalassemia patients and serve as an alternative to ruxolitinib (conventional medications). The pharmacokinetic profile of the ligand is predicted according to Lipinski's rule, while the binding energy (ΔG), initiation constant, and chemical bonds are examined using molecular docking with AutoDock v.4.25. This study successfully determined that brazilin, with a binding energy of -8.37 kcal/mol, is comparable to ruxolitinib, which has a binding energy of -8.71 kcal/mol. This finding shows that brazilin derived from sappan wood contains bioactive chemicals with potential JAK2 inhibitory activities. This finding establishes a foundation for further research aimed at developing new therapeutic agents for the treatment of splenomegaly in β-thalassemia and associated disorders.

Downloads

Download data is not yet available.

References

Adianingsih, O. R., Khasanah, U., Anandhy, K. D., & Yurina, V. (2022). In silico ADME-T and molecular docking study of phytoconstituents from Tithonia diversifolia (Hemsl.) A. Gray on various targets of diabetic nephropathy. J Pharm Pharmacogn Res, 10(4), 571-594.

Agosto, N. J. B. (2024). In silico molecular docking and ADMET prediction of Ginkgo biloba biflavonoids as dual inhibitors of human HMG-CoA reductase and alpha-amylase. Journal of the Serbian Chemical Society(00), 104-104.

Aldosari, S., Egbuna, C., Albadrani, H., Alshareeda, A., Patrick-Iwuanyanwu, K. C., Kamoru, A. A., Imodoye, S. O., Onyeike, E. N., Jahan, S., & Khan, J. (2023). Multi-Fold Computational Analysis to Explore JAK2 and STAT5 Potential Inhibitors for Modulation of Cancer.

Aldulaimi, S., & Mendez, A. M. (2021). Splenomegaly: diagnosis and management in adults. American Family Physician, 104(2), 271-276.

Amid, A., & Merkeley, H. (2023). SPLENOMEGALY AND SPLENECTOMY. In Guidelines for the Management of α-Thalassaemia [Internet]. Thalassaemia International Federation.

Asnawi, A., Nedja, M., Febrina, E., & Purwaniati, P. (2023). Prediction of a Stable Complex of Compounds in the Ethanol Extract of Celery Leaves (Apium graveolens L.) Function as a VKORC1 Antagonist. Tropical Journal of Natural Product Research, 7(2).

Brissot, P. (2016). Optimizing the diagnosis and the treatment of iron overload diseases. Expert review of gastroenterology & hepatology, 10(3), 359-370.

Buzelé, R., Barbier, L., Sauvanet, A., & Fantin, B. (2016). Medical complications following splenectomy. Journal of visceral surgery, 153(4), 277-286.

Casu, C., Oikonomidou, P. R., Presti, V. L., Aghajan, M., Guo, S., Osheiza, A., Melchiori, L., Ramos, P., & Rivella, S. (2016). Potential therapeutic applications of Jak2 inhibitors and Hif2a-ASO for the treatment of β-thalassemia intermedia and major. Blood, 128(22), 1012.

Casu, C., Pettinato, M., Liu, A., Aghajan, M., Lo Presti, V., Lidonnici, M. R., Munoz, K. A., O’Hara, E., Olivari, V., & Di Modica, S. M. (2020). Correcting β-thalassemia by combined therapies that restrict iron and modulate erythropoietin activity. Blood, The Journal of the American Society of Hematology, 136(17), 1968-1979.

Casu, C., Presti, V. L., Oikonomidou, P. R., Melchiori, L., Abdulmalik, O., Ramos, P., & Rivella, S. (2018). Short-term administration of JAK2 inhibitors reduces splenomegaly in mouse models of β-thalassemia intermedia and major. Haematologica, 103(2), e46.

Chamata, Y., Watson, K. A., & Jauregi, P. (2020). Whey-derived peptides interactions with ACE by molecular docking as a potential predictive tool of natural ACE inhibitors. International Journal of Molecular Sciences, 21(3), 864.

Cui, F., Sun, J., Mi, H., Li, B., Tang, L., Wang, R., Du, Y., Guo, B., Li, Y., & Shi, M. (2023). Chronic intermittent hypobaric hypoxia improves iron metabolism disorders via the IL-6/JAK2/STAT3 and Epo/STAT5/ERFE signaling pathways in metabolic syndrome rats. Journal of Trace Elements in Medicine and Biology, 79, 127259.

De Sanctis, V., Kattamis, C., Canatan, D., Soliman, A. T., Elsedfy, H., Karimi, M., Daar, S., Wali, Y., Yassin, M., & Soliman, N. (2017). β-thalassemia distribution in the old world: an ancient disease seen from a historical standpoint. Mediterranean Journal of Hematology and Infectious Diseases, 9(1).

Deshmukh, H. S., Adole, V. A., Kumar, A., Misra, N., Pawar, S. D., Tambe, S. R., & Jagdale, B. S. (2024). Synthesis, spectroscopic (IR and NMR), HOMO-LUMO, NLO, molecular docking and ADME study of (E)-2-(2-((5-chloro-3-methyl-1-phenyl-1H-pyrazol-4-yl) methylene) hydrazineyl)-4-(4-nitrophenyl) thiazole. Journal of Molecular Structure, 1305, 137745.

Ekowati, J., Tejo, B. A., Maulana, S., Kusuma, W. A., Fatriani, R., Ramadhanti, N. S., Norhayati, N., Nofianti, K. A., Sulistyowaty, M. I., & Zubair, M. S. (2023). Potential Utilization of Phenolic Acid Compounds as Anti-Inflammatory Agents through TNF-α Convertase Inhibition Mechanisms: A Network Pharmacology, Docking, and Molecular Dynamics Approach. ACS omega, 8(49), 46851-46868.

Fahmideh, H., Shapourian, H., Moltafeti, R., Tavakol, C., Forghaniesfidvajani, R., Zalpoor, H., & Nabi-Afjadi, M. (2022). The role of natural products as inhibitors of JAK/STAT signaling pathways in glioblastoma treatment. Oxidative medicine and cellular longevity, 2022(1), 7838583.

Fakhruri, M., & Rahmayanti, Y. (2021). Potensi fitokimia citrus aurantium (hesperetin, naringenin) dalam menghambat xantin okisidase pada hiperurisemia secara in silico. Jurnal Health Sains, 2(1), 79-89.

Galy, B., Conrad, M., & Muckenthaler, M. (2024). Mechanisms controlling cellular and systemic iron homeostasis. Nature Reviews Molecular Cell Biology, 25(2), 133-155.

Inamoto, Y., & Lee, S. J. (2017). Late effects of blood and marrow transplantation. Haematologica, 102(4), 614.

Indratmoko, S., Nurani, L. H., Wahyuningsih, I., Murti, T. D., & Setiyabudi, L. (2023). Effectiveness of Active Compounds of Herbal Plants as Aphrodisiacs Through Molecular Docking Against Human Phosphodiesterase-5 Receptors.

Intan, A. E. K., & Silvia, M. (2021). Pharmacological activities of Caesalpinia sappan. Infokes, 11(1), 363-370.

Kalontong, P. K., Safithri, M., & Tarman, K. (2022). Penambatan molekul senyawa aktif Spirulina platensis sebagai Inhibitor TMPRSS2 untuk Mencegah Infeksi SARS-COV-2. Jurnal Pengolahan Hasil Perikanan Indonesia, 25(2), 253-267.

Kamble, R. P., Ghosh, P., & Kulkarni, A. A. (2022). Identification of α-amylase inhibitory compounds from leaves of Careya arborea Roxb. and in silico docking studies. South African Journal of Botany, 151, 493-503.

Khalili, M., & Ebrahimzadeh, M. A. (2015). A review on antioxidants and some of their common evaluation methods. Journal of Mazandaran University of Medical Sciences, 24(120), 188-208.

Khan, L., Verma, S. L., Shukla, T., Kala, C., & Chandra, T. (2023). Alloimmunization and iron overload in thalassemia patients in North India: A prospective observational study. Asian Journal of Transfusion Science.

Kusuma, W., Maretha, S., Utomo, D. H., & Susanti, R. (2022). Molecular Mechanism of Inhibition of Cell Proliferation: An In Silico Study of the Active Compounds in Curcuma longa as an Anticancer. Journal of Tropical Biodiversity & Biotechnology, 7(3).

Lipinski, C. A. (2016). Rule of five in 2015 and beyond: Target and ligand structural limitations, ligand chemistry structure and drug discovery project decisions. Advanced drug delivery reviews, 101, 34-41.

Mardianingrum, R., Endah, S. R. N., Suhardiana, E., Ruswanto, R., & Siswandono, S. (2021). Docking and molecular dynamic study of isoniazid derivatives as anti-tuberculosis drug candidate. Chemical Data Collections, 32, 100647.

Margono, R. S., & Sumiati, T. (2019). Potensi tanaman Indonesia sebagai antidiabetes melalui mekanisme penghambatan enzim α-glukosidase. Jurnal Farmamedika (Pharmamedika Journal), 4(2), 86-92.

Maskoen, A. M., & Safitrie, R. (2018). Iron chelation ability and haematological effect of Sappan wood (Caesalpinia sappan, L.) extract tablet on iron overload rats. Asian Journal of Medicine and Biomedicine, 2-2.

Mekala, K., & Radha, R. (2015). A review on sappan wood-a therapeutic dye yielding tree. Research Journal of Pharmacognosy and Phytochemistry, 7(4), 227-231.

Mizher, E. A. (2024). Immunological Changes and Complement Proteins in Major Thalassemia Patients Proteins Post-Splenectomy. Academia Open, 9(2).

Mobarra, N., Shanaki, M., Ehteram, H., Nasiri, H., Sahmani, M., Saeidi, M., Goudarzi, M., Pourkarim, H., & Azad, M. (2016). A review on iron chelators in treatment of iron overload syndromes. International journal of hematology-oncology and stem cell research, 10(4), 239.

Mustarichie, R., Megantara, S., & Saptarini, N. (2017). In-silico study of bioactive compounds of natural materials as a JAK-signal transducer and activator of transcription inhibitor for anti-alopecia. Asian J Pharm Clin Res, 10(11), 331-336.

Narahari, J. M., Guruswamy, P., Jagadeesha, N. M., Shivashakar, K. K., Kumar, D. P., Narayana, P. S., Vishwanath, P. M., & Prashant, A. (2024). Exploring the Impact of Iron Overload on Mitochondrial DNA in β-Thalassemia: A Comprehensive Review. Gene Expression(000), 0-0.

Nguyen Vo, T. H., Tran, N., Nguyen, D., & Le, L. (2016). An in silico study on antidiabetic activity of bioactive compounds in Euphorbia thymifolia Linn. SpringerPlus, 5, 1-13.

Nirmal, N. P., & Panichayupakaranant, P. (2015). Antioxidant, antibacterial, and anti-inflammatory activities of standardized brazilin-rich Caesalpinia sappan extract. Pharmaceutical Biology, 53(9), 1339-1343.

Oikonomidou, P. R., & Rivella, S. (2018). What can we learn from ineffective erythropoiesis in thalassemia? Blood reviews, 32(2), 130-143.

Peffault de Latour, R. (2016). Transplantation for bone marrow failure: current issues. Hematology 2014, the American Society of Hematology Education Program Book, 2016(1), 90-98.

Pitaloka, R., Alipin, K., Syamsunarno, M., Utama, G., Panigoro, R., & Safitri, R. (2022). Sappan wood ethanol extract (Caesalpinia sappan L.) As adjuvant and substitute of iron chelator in acute iron overload rat model. Adv. Anim. Vet. Sci, 10(12), 2589-2595.

Prottoy, N. I., Sarkar, B., Ullah, A., Hossain, S., Boby, A. S., & Araf, Y. (2019). Molecular docking and pharmacological property analysis of antidiabetic agents from medicinal plants of bangladesh against type II diabetes: a computational approach. PharmaTutor, 7(9), 6-15.

Purnama, J. N., Khristian, E., Syamsunarno, M. R. A., Panigoro, R., & Safitri, R. (2022). The Effect of Sappan Wood Extract (Caesalpinia sappan L.) on Fetal and Placenta Histopathology of White Rat. Jurnal Veteriner, 23(2).

Ruswanto, R., Nofianti, T., Lestari, T., Septian, A. D., Firmansyah, A. P., & Mardianingrum, R. (2024). Potential Active Compounds of Propolis as Breast Anticancer Candidates: In Silico Study. Jordan Journal of Biological Sciences, 17(1).

Safitri, R., Malini, D., Maskoen, A., Reniarti, L., Syamsunarno, M., & Panigoro, R. (2017). Iron-chelating effect of Caesalpinia sappan extract under conditions of iron overload. In Advances in Biomolecular Medicine (pp. 87-92). Crc Press.

Safitri, R., Maskoen, A. M., Syamsunarno, M. R. A. A., Ghozali, M., & Panigoro, R. (2018). Iron chelating activity of Caesalpinia sappan L. extract on iron status in iron overload rats (Rattus norvegicus L.). AIP Conference Proceedings,

Sari, R., & Suhartati, S. (2016). Secang (Caesalpinia sappan L.): Tumbuhan herbal kaya antioksidan. Buletin Eboni, 13(1), 57-67.

Siregar, M., Awaluddin, A., Nurnahari, N., Nur, S., Febrina, E., & Asnawi, A. (2020). MOLECULAR DOCKING AND MOLECULAR DYNAMIC SIMULATION OF THE AGLYCONE OF CURCULIGOSIDE A AND ITS DERIVATIVES AS ALPHA GLUCOSIDASE INHIBITORS. Rasayan Journal of Chemistry, 13(1).

Subahi, E. A., Ata, F., Choudry, H., Iqbal, P., AlHiyari, M. A., Soliman, A. T., De Sanctis, V., & Yassin, M. A. (2022). Extramedullary haematopoiesis in patients with transfusion dependent β-thalassaemia (TDT): a systematic review. Annals of Medicine, 54(1), 764-774.

Suttorp, M., & Classen, C. F. (2021). Splenomegaly in children and adolescents. Frontiers in pediatrics, 9, 704635.

Syamsunarno, M. R. A., Safitri, R., & Kamisah, Y. (2021). Protective Effects of Caesalpinia sappan Linn. and Its Bioactive Compounds on Cardiovascular Organs. Front Pharmacol, 12, 725745. https://doi.org/10.3389/fphar.2021.725745

Taher, A. T., Musallam, K. M., & Cappellini, M. D. (2023). INEFFECTIVE ERYTHROPIESIS AND ANAEMIA. In Guidelines for the Management of Non-Transfusion-Dependent β-Thalassaemia [Internet]. 3rd edition. Thalassaemia International Federation.

Tuyen, T. T., Bach, P. C., Hai, H. V., Minh, P. T. H., Van, N. T. H., & Quan, P. M. (2023). In silico studies on potential MCF-7 inhibitors of alkaloid and phenolic compounds isolated from Zanthoxylum nitidum: A combination of molecular docking and admet analysis. Vietnam Journal of Science and Technology, 61(3), 355-364.

Vaziri-Amjad, S., Rahgosha, R., & Taherkhani, A. (2024). Potential JAK2 Inhibitors from Selected Natural Compounds: A Promising Approach for Complementary Therapy in Cancer Patients. Evidence‐Based Complementary and Alternative Medicine, 2024(1), 1114928.

Vázquez-Jiménez, L. K., Rivera, G., Juárez-Saldivar, A., Ortega-Balleza, J. L., Ortiz-Pérez, E., Jaime-Sánchez, E., Paz-González, A., & Lara-Ramírez, E. E. (2024). Biological Evaluations and Computer-Aided Approaches of Janus Kinases 2 and 3 Inhibitors for Cancer Treatment: A Review. Pharmaceutics, 16(9), 1165.

Vij, T., Anil, P. P., Shams, R., Dash, K. K., Kalsi, R., Pandey, V. K., Harsányi, E., Kovács, B., & Shaikh, A. M. (2023). A Comprehensive review on bioactive compounds found in Caesalpinia sappan. Molecules, 28(17), 6247.

Wang, X., Li, Y., Han, L., Li, J., Liu, C., & Sun, C. (2021). Role of flavonoids in the treatment of iron overload. Frontiers in cell and developmental biology, 9, 685364.

Weni, M., Safithri, M., & Seno, D. S. H. (2020). Molecular Docking of Active Compounds Piper crocatum on the A-Glucosidase Enzyme as Antidiabetic. Indonesian Journal of Pharmaceutical Science and Technology, 7(2), 64-72.

Xue, Q., Liu, X., Russell, P., Li, J., Pan, W., Fu, J., & Zhang, A. (2022). Evaluation of the binding performance of flavonoids to estrogen receptor alpha by Autodock, Autodock Vina and Surflex-Dock. Ecotoxicology and Environmental Safety, 233, 113323.

Yadav, A., Kumari, R., Yadav, A., Mishra, J., Srivatva, S., & Prabha, S. (2016). Antioxidants and its functions in human body-A Review. Res. Environ. Life Sci, 9(11), 1328-1331.

Yadav, P. K., & Singh, A. K. (2022). A review of iron overload in beta-thalassemia major, and a discussion on alternative potent iron chelation targets. Plasmatology, 16, 26348535221103560.