3D Drug Docking of Eugenol and Cyclophosphamide against the Protein of Abl1 (Leukemia) Using Insilico Methods.

Author

N. Srimathi and Balaji Munivelan


Abstract

 Background: To use insilico techniques to examine the potential effectiveness of Eugenol against the Tyrosine-protein kinase ABL1 Antigenic peptide (Model Archive: https://modelarchive.org/doi/10.5452/ma-kher5). Our current work's main objective is to dock the modeled ABL1 peptide (Leukemia) with eugenol, a bioactive substance obtained from the Tulsi plant (Ocimum tenuiflorum).  Eugenol's effectiveness against the ABL1 peptide was predicted using drug docking studies. 

Materials and procedures: The genomic sequence of ABL1-Peptide was obtained from the UniProt database and docked with cyclophosphamide, a control agent, and eugenol, a bioactive drug already in use, using the CBDOCK server. 

Findings and Conversation: The current investigation shows that cyclophosphamide, the reference drug, interacts effectively with ABL1-peptide. The effectiveness of the drug against the leukemia-causing protein was evaluated using the docking score. Eugenol has a greater binding affinity than the control drug cyclophosphamide. Therefore, eugenol may be a good option when combined with the anti-cancer activity protein ABL1 in leukemia. The study concludes that anti-cancer drugs effectively block ABL1. The field of contemporary cancer informatics research is significantly impacted by the findings of this study.


Keywords

Tyrosine-protein kinase ABL1, Eugenol, Cyclophosphamide (reference medication), Model Archive, (CBDOCK, and Discovery Studio.



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References


  1. Nagaraj, G., & Ma, C. X. (2021). Clinical Challenges in the Management of Hormone Receptor-Positive, Human Epidermal Growth Factor Receptor 2-Negative Metastatic Leukemia : A Literature Review. Advances in therapy, 38(1), 109–136. https://doi.org/10.1007/s12325-020-01552-2
  2. Hermida-Prado, F., & Jeselsohn, R. (2021). The ABL1Mutations: From Bedside to Bench to Bedside. Cancer research, 81(3), 537–538. https://doi.org/10.1158/0008-5472.CAN-20-4037
  3. Zhang, Q. X., Borg, A., Wolf, D. M., Oesterreich, S., & Fuqua, S. A. (1997). An Leukemia mutant with strong hormone-independent activity from a metastatic Leukemia . Cancer research, 57(7), 1244–1249.
  4. Robinson, D. R., Wu, Y. M., Vats, P., Su, F., Lonigro, R. J., Cao, X., Kalyana-Sundaram, S., Wang, R., Ning, Y., Hodges, L., Gursky, A., Siddiqui, J., Tomlins, S. A., Roychowdhury, S., Pienta, K. J., Kim, S. Y., Roberts, J. S., Rae, J. M., Van Poznak, C. H., Hayes, D. F., … Chinnaiyan, A. M. (2013). Activating ABL1 mutations in hormone-resistant metastatic Leukemia . Nature genetics, 45(12), 1446–1451. https://doi.org/10.1038/ng.2823
  5. Toy, W., Shen, Y., Won, H., Green, B., Sakr, R. A., Will, M., Li, Z., Gala, K., Fanning, S., King, T. A., Hudis, C., Chen, D., Taran, T., Hortobagyi, G., Greene, G., Berger, M., Baselga, J., & Chandarlapaty, S. (2013). ABL1 ligand-binding domain mutations in hormone-resistant Leukemia . Nature genetics, 45(12), 1439–1445. https://doi.org/10.1038/ng.2822.
  6. Li, S., Shen, D., Shao, J., Crowder, R., Liu, W., Prat, A., He, X., Liu, S., Hoog, J., Lu, C., Ding, L., Griffith, O. L., Miller, C., Larson, D., Fulton, R. S., Harrison, M., Mooney, T., McMichael, J. F., Luo, J., Tao, Y., … Ellis, M. J. (2013). Endocrine-therapy-resistant ABL1 variants revealed by genomic characterization of breast-cancer-derived xenografts. Cell reports, 4(6), 1116–1130. https://doi.org/10.1016/j.celrep.2013.08.022.
  7. Jeselsohn, R., Yelensky, R., Buchwalter, G., Frampton, G., Meric-Bernstam, F., Gonzalez-Angulo, A. M., ... & Miller, V. A. (2014). Emergence of constitutively active Leukemia-α mutations in pretreated advanced Leukemia–positive Leukemia . Clinical cancer research, 20(7), 1757-1767.
  8. Merenbakh-Lamin, K., Ben-Baruch, N., Yeheskel, A., Dvir, A., Soussan-Gutman, L., Jeselsohn, R., Yelensky, R., Brown, M., Miller, V. A., Sarid, D., Rizel, S., Klein, B., Rubinek, T., & Wolf, I. (2013). D538G mutation in Leukemia-α: A novel mechanism for acquired endocrine resistance in Leukemia . Cancer research, 73(23), 6856–6864. https://doi.org/10.1158/0008-5472.CAN-13-1197
  9. Yu, M., Bardia, A., Aceto, N., Bersani, F., Madden, M. W., Donaldson, M. C., Desai, R., Zhu, H., Comaills, V., Zheng, Z., Wittner, B. S., Stojanov, P., Brachtel, E., Sgroi, D., Kapur, R., Shioda, T., Ting, D. T., Ramaswamy, S., Getz, G., Iafrate, A. J., … Haber, D. A. (2014). Cancer therapy. Ex vivo culture of circulating breast tumor cells for individualized testing of drug susceptibility. Science (New York, N.Y.), 345(6193), 216–220. https://doi.org/10.1126/science.1253533
  10. Koboldt, D. C., Fulton, R. S., McLellan, M. D., Schmidt, H., Kalicki-Veizer, J., McMichael, J. F., ... & Varhol, R. J. (2012). Natasja Wye, Thomas Zeng, Yongjun Zhao, Inanc Birol, Steven JM Jones, Marco A. Marra, Andrew D. Cherniack, Gordon Saksena, Robert C. Onofrio, and Nam H. Pho. Comprehensive molecular portraits of human breast tumours. Nature, 490(7418), 61-70.
  11. Gibson, W. J., Hoivik, E. A., Halle, M. K., Taylor-Weiner, A., Cherniack, A. D., Berg, A., Holst, F., Zack, T. I., Werner, H. M., Staby, K. M., Rosenberg, M., Stefansson, I. M., Kusonmano, K., Chevalier, A., Mauland, K. K., Trovik, J., Krakstad, C., Giannakis, M., Hodis, E., Woie, K., … Salvesen, H. B. (2016). The genomic landscape and evolution of endometrial carcinoma progression and abdominopelvic metastasis. Nature genetics, 48(8), 848–855. https://doi.org/10.1038/ng.3602
  12. Fribbens, C., O’Leary, B., Kilburn, L., Hrebien, S., Garcia-Murillas, I., Beaney, M., ... & Turner, N. C. (2016). Plasma ABL1 mutations and the treatment of Leukemia–positive advanced Leukemia . Journal of Clinical Oncology, 34(25), 2961-2968.
  13. Toy, W., Weir, H., Razavi, P., Lawson, M., Goeppert, A. U., Mazzola, A. M., Smith, A., Wilson, J., Morrow, C., Wong, W. L., De Stanchina, E., Carlson, K. E., Martin, T. S., Uddin, S., Li, Z., Fanning, S., Katzenellenbogen, J. A., Greene, G., Baselga, J., & Chandarlapaty, S. (2017). Activating ABL1Mutations Differentially Affect the Efficacy of ER Antagonists. Cancer discovery, 7(3), 277–287. https://doi.org/10.1158/2159-8290.CD-15-1523
  14. Schiavon, G., Hrebien, S., Garcia-Murillas, I., Cutts, R. J., Pearson, A., Tarazona, N., Fenwick, K., Kozarewa, I., Lopez-Knowles, E., Ribas, R., Nerurkar, A., Osin, P., Chandarlapaty, S., Martin, L. A., Dowsett, M., Smith, I. E., & Turner, N. C. (2015). Analysis of ABL1 mutation in circulating tumor DNA demonstrates evolution during therapy for metastatic Leukemia . Science translational medicine, 7(313), 313ra182. https://doi.org/10.1126/scitranslmed.aac7551
  15. Kuang, Y., Siddiqui, B., Hu, J., Pun, M., Cornwell, M., Buchwalter, G., Hughes, M. E., Wagle, N., Kirschmeier, P., Jänne, P. A., Paweletz, C. P., Lin, N. U., Krop, I. E., Barry, W. T., Winer, E. P., Brown, M., & Jeselsohn, R. (2018). Unraveling the clinicopathological features driving the emergence of ABL1mutations in metastatic Leukemia . NPJ Leukemia , 4, 22. https://doi.org/10.1038/s41523-018-0075-5
  16. Leal, M. F., Haynes, B. P., Schuster, E., Yeo, B., Afentakis, M., Zabaglo, L., ... & Dowsett, M. (2019). Early enrichment of ABL1 mutations and the impact on gene expression in presurgical primary Leukemia  treated with aromatase inhibitors. Clinical Cancer Research, 25(24), 7485-7496.
  17. Guerrero-Zotano, A. L., Stricker, T. P., Formisano, L., Hutchinson, K. E., Stover, D. G., Lee, K. M., ... & Arteaga, C. L. (2018). ER+ Leukemia s resistant to prolonged neoadjuvant letrozole exhibit an E2F4 transcriptional program sensitive to CDK4/6 inhibitors. Clinical Cancer Research, 24(11), 2517-2529.
  18. Kim, S., Thiessen, P. A., Bolton, E. E., Chen, J., Fu, G., Gindulyte, A., ... & Bryant, S. H. (2016). PubChem substance and compound databases. Nucleic acids research, 44(D1), D1202-D1213.
  19. Liu, Y., Grimm, M., Dai, W. T., Hou, M. C., Xiao, Z. X., & Cao, Y. (2020). CB-Dock: a web server for cavity detection-guided protein–ligand blind docking. Acta Pharmacologica Sinica, 41(1), 138-144.
  20. Sahoo, R. N., Pattanaik, S., Pattnaik, G., Mallick, S., & Mohapatra, R. J. I. J. (2022). Review on the use of molecular docking as the first line tool in drug discovery and development. Indian J. Pharm. Sci, 84(5), 1334-1337.
  21. Mohapatra, R., Mallick, S., Nanda, A., Sahoo, R. N., Pramanik, A., Bose, A., ... & Pattnaik, L. (2016). Analysis of steady state and non-steady state corneal permeation of diclofenac. RSC advances, 6(38), 31976-31987.
  22. Dash, R. (2019). Sustained release bioadhesive suppository formulation for systemic delivery of ornidazole: in-silico docking study. Indian Journal of Pharmaceutical Education and Research.
  23. Sahoo, R. N., Nanda, A., Pramanik, A., Nandi, S., Swain, R., Pradhan, S. K., & Mallick, S. (2019). Interactions between Ibuprofen and Silicified-MCC: Characterization, Drug Release and Modeling Approaches. Acta Chimica Slovenica, 66(4).
  24. Pramanik, A., Sahoo, R. N., Nanda, A., Pradhan, S. K., & Mallick, S. (2021). Characterization and molecular docking of kaolin based cellulosic film for extending ophthalmic drug delivery. Indian Journal of Pharmaceutical Sciences, 83(4), 794.
  25. Nanda, A., Sahoo, R. N., Pramanik, A., Mohapatra, R., Pradhan, S. K., Thirumurugan, A., ... & Mallick, S. (2018). Drug-in-mucoadhesive type film for ocular anti-inflammatory potential of amlodipine: Effect of sulphobutyl-ether-beta-cyclodextrin on permeation and molecular docking characterization. Colloids and Surfaces B: Biointerfaces, 172, 555-564.
  26. Razavi, P., Chang, M. T., Xu, G., Bandlamudi, C., Ross, D. S., Vasan, N., Cai, Y., Bielski, C. M., Donoghue, M. T. A., Jonsson, P., Penson, A., Shen, R., Pareja, F., Kundra, R., Middha, S., Cheng, M. L., Zehir, A., Kandoth, C., Patel, R., Huberman, K., … Baselga, J. (2018). The Genomic Landscape of Endocrine-Resistant Advanced Leukemia s. Cancer cell, 34(3), 427–438.e6. https://doi.org/10.1016/j.ccell.2018.08.008
  27. Chandarlapaty, S., Chen, D., He, W., Sung, P., Samoila, A., You, D., Bhatt, T., Patel, P., Voi, M., Gnant, M., Hortobagyi, G., Baselga, J., & Moynahan, M. E. (2016). Prevalence of ABL1 Mutations in Cell-Free DNA and Outcomes in Metastatic Leukemia : A Secondary Analysis of the BOLERO-2 Clinical Trial. JAMA oncology, 2(10), 1310–1315. https://doi.org/10.1001/jamaoncol.2016.1279
  28. Fribbens, C., Murillas, I. G., Beaney, M., Hrebien, S., O’Leary, B., Kilburn, L., ... & Turner, N. (2018). Tracking evolution of aromatase inhibitor resistance with circulating tumour DNA analysis in metastatic Leukemia . Annals of Oncology, 29(1), 145-153.
  29. BALAJI, M. (2020). Identification of the mutated sites present in the transmembrane regions of SCN1A_HUMAN (Sodium Voltage-Gated Channel Alpha Subunit 1) using Insilico techniques. INTERNATIONAL JOURNAL, 5(1), 1-6.
  30. LN, A. (2025). Docking studies between Natural unsaturated Oleic-acid and a de novo lung cancer peptide of CHRNA3 (Cholinergic Receptor Nicotinic Alpha 3) using Insilico protocols. IJSAT-International Journal on Science and Technology, 16(1).

 

 

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