Exploring the Potential of Allium sativum Phytocompounds as B-Cell Leukemia 2 Inhibitors in Acute Lymphoblastic Leukemia: Molecular Docking Study

Year : 2024 | Volume : 13 | Issue : 02 | Page : 53 80
    By

    Santhiya K.,

  1. Student, Department of Bioinformatics, Bionome, Bengaluru, Karnataka, India

Abstract

Objective: Acute lymphoblastic leukemia (ALL) is a lymphoid progenitor cell malignancy that could be treated with plant-based drugs, thus alleviating the off-target effects caused by conventional chemotherapy. Since ancient days, Allium sativum has been an integral part of traditional medicine and an excellent antimicrobial, antioxidant, and antiproliferative agent. Hence, this study aims to assess the anti-leukemic potential of A. sativum phytoconstituents as the B-cell leukemia 2 protein (Bcl-2) natural inhibitor drug. Methods: 25 phytoconstituents of A. sativum were subjected to screening of pharmacological properties, drug-likeliness, toxicity, and absorption, distribution, metabolism, and excretion (ADME) characteristics using SwissADME and ADMET 2.0 tools, respectively, for their potential to serve as drug leads or ligands. Bcl-2 protein, a B-cell apoptosis regulator, along with their homologous chains A, B, C, D, E, and F are extracted from the Protein Data Bank (PDB) and purified using the protein visualizer tool Discovery Studio. The A. sativum ligands and Bcl-2 target were docked by the PyRx tool. Results: The target protein stability and conformation were predicted by 93% percentage favored regions of amino acids in the Ramachandran plot obtained through different combinations of phi and psi angles. Overall, five ligands of A. sativum, namely kaempferol, quercetin, 1-ethylquinolinium iodide, carvacrol, and eugenol, had the best binding affinities with target protein Bcl-2 with acceptable ADME ranges and other properties, thereby promoting them as safe drug candidates. Conclusion: The renowned anti-cancerous properties of kaempferol, quercetin, 1-ethyl quinolinium iodide, carvacrol, and eugenol are proven to inhibit the Bcl-2 target protein in ALL through these molecular interactions

Keywords: Allium sativum, anti-leukemic, Bcl-2 protein, acute lymphoblastic leukemia, molecular docking, phytocompounds, ADME screening, Bcl-2 inhibitors

[This article belongs to Research & Reviews : Journal of Computational Biology ]

How to cite this article:
Santhiya K.. Exploring the Potential of Allium sativum Phytocompounds as B-Cell Leukemia 2 Inhibitors in Acute Lymphoblastic Leukemia: Molecular Docking Study. Research & Reviews : Journal of Computational Biology. 2024; 13(02):53-80.
How to cite this URL:
Santhiya K.. Exploring the Potential of Allium sativum Phytocompounds as B-Cell Leukemia 2 Inhibitors in Acute Lymphoblastic Leukemia: Molecular Docking Study. Research & Reviews : Journal of Computational Biology. 2024; 13(02):53-80. Available from: https://journals.stmjournals.com/rrjocb/article=2024/view=180805


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References

1. Terwilliger T, Abdul-Hay M. Acute lymphoblastic leukemia: a comprehensive review and 2017 update. Blood Cancer J. 2007;7(6):e577–e577. doi:10.1038/bcj.2017.53.
2. Abiri B, Kelishadi R, Sadeghi H, Azizi-Soleiman F. Effects of maternal diet during pregnancy on the risk of childhood acute lymphoblastic leukemia: a systematic review. Nutrition and cancer. 2016 Oct 2;68(7):1065–72.
3. Blanco-Lopez J, Iguacel I, Pisanu S, Almeida C, Steliarova-Foucher E, Sierens C, Huybrechts I. Role of maternal diet in the risk of childhood acute leukemia: A systematic review and meta-analysis. Int J Environ Res Public Health. 2023;20(7):5428. doi:10.3390/ijerph20075428.
4. Ekpa QL, Akahara PC, Anderson AM, Adekoya OO, Ajayi OO, Alabi PO, Okobi OE, Jaiyeola O, Ekanem MS. A review of acute lymphocytic leukemia (ALL) in the pediatric population: Evaluating current trends and changes in guidelines in the past decade. Cureus. 2023;15(12):e49930. doi:10.7759/cureus.49930.
5. Huang FL, Yu SJ, Li CL. Role of autophagy and apoptosis in acute lymphoblastic leukemia. Cancer Control. 2021;28. doi:10.1177/10732748211019.
6. Olivas-Aguirre M, Pottosin I, Dobrovinskaya O. Mitochondria as emerging targets for therapies against T cell acute lymphoblastic leukemia. J Leukoc Biol. 2019;105(5):935–946. doi:10.1002/
jlb.5vmr0818-330rr.
7. Hogarth LA, Hall AG. Increased BAX expression is associated with an increased risk of relapse in childhood acute lymphocytic leukemia. Blood. 1999:93(8):2671–2678. doi:10.1182/blood.V93.8.
2671.
8. Moazami-Goudarzi M, Farshdousti-Hagh M, Hoseinpour-Feizi A, Talebi M, Movassaghpour-Akbari AA, Shams-Asanjan K, Eyvazi-Ziyaee J, Seifi M. The acute lymphoblastic leukemia prognostic scoring whether it is possible by BCL-2, BAX gene promoter genotyping. Caspian J Intern Med. 2016;7(2):105–113.
9. Ghasemi A, Khanzadeh T, Heydarabad ZM, Khorrami A, Esfahlan AJ, Ghavipanjeh S, et al. Evaluation of BAX and BCL-2 gene expression and apoptosis induction in acute lymphoblastic leukemia cell line CCRFCEM after high-dose prednisolone treatment. Asian Pac J Cancer Prev. 2018;19(8):2319–2323. doi:10.22034/APJCP.2018.19.8.2319.
10. Iacovelli S, Ricciardi MR, Allegretti M, Mirabilii S, Licchetta R, Bergamo P, et al. Co-targeting of Bcl-2 and mTOR pathway triggers synergistic apoptosis in BH3 mimetics resistant acute lymphoblastic leukemia. Oncotarget. 2015;6(31):32089–32103. doi:10.18632/oncotarget.5156.
11. Tsujimoto Y, Finger LR, Yunis J, Nowell PC, Croce CM. Cloning of the chromosome breakpoint of neoplastic B cells with the t (14;18) chromosome translocation. Sci. 1984;226(4678):1097–1099. doi:10.1126/science.60932.
12. Tsujimoto Y, Jaffe E, Cossman J, Gorham J, Nowell PC, Croce CM. Clustering of breakpoints on chromosome 11 in human B-cell neoplasms with the t (11;14) chromosome translocation. Nat. 1985;315(6017):340–343. doi:10.1038/315340a0.
13. Korsmeyer SJ, Shutter JR, Veis DJ, Merry DE, Oltvai ZN. Bcl-2/Bax: A rheostat that regulates an anti-oxidant pathway and cell death. Semin Cancer Biol. 1993;4(6):327–332.
14. Jabbour E, O’Brien S, Konopleva M, Kantarjian H. New insights into the pathophysiology and therapy of adult acute lymphoblastic leukemia. Cancer. 2015;121(15):2517–2528. doi:10.1002/
cncr.29383.
15. Zhang Y, Liu X, Ruan J, Zhuang X, Zhang X, Li Z. Phytochemicals of garlic: Promising candidates for cancer therapy. Biomed Pharmacother. 2020;123:109730. doi:10.1016/j.biopha.2019.109730.
16. Szklarczyk D, Gable AL, Lyon D, Junge A, Wyder S, Huerta-Cepas J, Mering C. STRING v11: protein–protein association networks with increased coverage, supporting functional discovery in genome-wide experimental datasets. Nucleic Acids Res. 2019;47(D1):D607–D613. doi:10.1093/
nar/gky1131.
17. Berman HM. The Protein Data Bank. Nucleic Acids Res. 2000;28(1):235–242. doi:10.1093/nar/
28.1.235.
18. Zardecki C, Dutta S, Goodsell DS, Lowe R, Voigt M, Burley SK. PDB‐101: Educational resources supporting molecular explorations through biology and medicine. Protein Sci. 2022;31(1):129–140. doi:10.1002/pro.4200.
19. Baroroh U, Biotek M, Muscifa ZS, Destiarani W, Rohmatullah FG, Yusuf M. Molecular interaction analysis and visualization of protein-ligand docking using Biovia Discovery Studio Visualizer. Indones J Comput Biol. 2023;2(1):22–30.
20. Mohanraj K, Karthikeyan BS, Vivek-Ananth RP, Chand RPB, Aparna SR, Mangalapandi P, Samal A. IMPPAT: A curated database of Indian medicinal plants, phytochemistry and therapeutics. Sci Rep. 2018;8:4329. doi:10.1038/s41598-018-22631-z.
21. Kim S, Chen J, Cheng T, Gindulyte A, He J, He S, Li Q, Shoemaker BA, Thiessen PA, Yu B, Zaslavsky L. PubChem in 2021: new data content and improved web interfaces. Nucleic Acids Res. 2021;49(D1):D1388–D1395. doi:10.1093/nar/gkaa971.
22. Daina A, Michielin O, Zoete V. SwissADME: a free web tool to evaluate pharmacokinetics, drug-likeness and medicinal chemistry friendliness of small molecules. Sci Rep. 2017;7(1):42717. doi:10.1038/srep42717.
23. Wang H, Irigoyen S, Liu J, Ramasamy M, Padilla C, Bedre R, Yang C, Thapa SP, Mulgaonkar N, Ancona V, He P, Coaker G, Fernando S, Mandadi KK. Inhibition of a conserved bacterial dual-specificity phosphatase confers plant tolerance to Candidatus liberibacter spp. iSci. 2024;27(3): 109232. doi:10.1016/j.isci.2024.109232.
24. Xiong G, Wu Z, Yi J, Fu L, Yang Z, Hsieh C, Yin M, Zeng X, Wu C, Lu A, Chen X, Hou T, Cao D. ADMETlab 2.0: an integrated online platform for accurate and comprehensive predictions of ADMET properties. Nucleic acids Res. 2021;49(W1):W5–W14. doi:10.1093/nar/gkab255.
25. Gadaleta D, Vuković K, Toma C, Lavado GJ, Karmaus AL, Mansouri K, Kleinstreuer NC, Benfenati E, Roncaglioni A. SAR and QSAR modeling of a large collection of LD50 rat acute oral toxicity data. J Cheminform. 2019;11(1):58. doi:10.1186/s13321-019-0383-2.
26. Kondapuram SK, Sarvagalla S, Coumar MS. Docking-Based Virtual Screening using PyRx Tool: Autophagy Target Vps34 as a Case Study. In: Coumar MS, editor. Molecular Docking for Computer-Aided Drug Design. United States: Academic Press; 2021. 463–477. doi:10.1016/
C2019-0-04960-6.
27. Devaurs D, Antunes DA, Hall-Swan S, Mitchell N, Moll M, Lizée G, Kavraki LE. Using parallelized incremental meta-docking can solve the conformational sampling issue when docking large ligands to proteins. BMC Mol Cell Biol. 2019;20:1–5. doi:10.1186/s12860-019-0218-z.
28. Kelekar A, Chang BS, Harlan JE, Fesik SW, Thompson CB. Bad is a BH3 domain-containing protein that forms an inactivating dimer with Bcl-XL. Mol Cell Biol. 1997;17(12):7040–7046. doi:10.1128/MCB.17.12.7040.
29. Yang E, Zha J, Jockel J, Boise LH, Thompson CB, Korsmeyer SJ. Bad, a heterodimeric partner for Bcl-XL and Bcl-2, displaces bax and promotes cell death. Cell Press. 1995;80(2):285–291.
30. Strasser A. The role of BH3-only proteins in the immune system. Nat Rev Immunol. 2005;5(3):189–200. doi:10.1038/nri1568.
31. Lee AJ, Liao HJ, Hong JR. Overexpression of Bcl2 and Bcl2L1 can suppress Betanodavirus-induced type III cell death and autophagy induction in GF-1 cells. Symmetry. 2022;14(2):360. doi:10.3390/sym14020360.
32. Marquez RT, Xu L. Bcl-2: Beclin 1 complex: multiple, mechanisms regulating autophagy/apoptosis toggle switch. Am J Cancer Res. 2012;(2):214–221.
33. Burton TR, Gibson SB. The role of Bcl-2 family member BNIP3 in cell death and disease: NIPping at the heels of cell death. Cell Death Differ. 2009;16(4):515–523. doi:10.1038/cdd.2008.185.
34. Li X, Miao X, Wang H, Xu Z, Li B. The tissue dependent interactions between p53 and Bcl-2 in vivo. Oncotarget. 2015;6(34):35699–35709. doi:10.18632/oncotarget.5372.
35. Kanehisa M, Goto S. KEGG: kyoto encyclopedia of genes and genomes. Nucleic Acids Res. 2000;28(1):27–30. doi:10.1093/nar/28.1.27.
36. Laskowski RA, Jabłońska J, Pravda L, Vařeková RS, Thornton JM. PDBsum: Structural summaries of PDB entries. Protein Sci. 2018;27(1):129–134. doi:10.1002/pro.3289.
37. Alberts B, Johnson A, Lewis J, Raff M, Roberts K, Walter P. Molecular Biology of the Cell. 4th edition. New York: Garland Science; 2002.
38. Li W, Cowley A, Uludag M, Gur T, McWilliam H, Squizzato S, Park YM, Buso N, Lopez R. The EMBL-EBI bioinformatics web and programmatic tools framework. Nucleic Acids Res. 2015;43(W1):W580–W584. doi:10.1093/nar/gkv279.
39. Mehrotra S, Bg PK, Nayak PG, Joseph A, Manikkath J. Recent progress in the oral delivery of therapeutic peptides and proteins: overview of pharmaceutical strategies to overcome absorption hurdles. Adv Pharm Bull. 2023;14(1):11–33. doi:10.34172/apb.2024.009.
40. Ranjith D, Ravikumar C. SwissADME predictions of pharmacokinetics and drug-likeness properties of small molecules present in Ipomoea mauritiana Jacq. J Pharmacogn Phytochem. 2019;8(5):2063–2073.
41. Jendele L, Krivak R, Skoda P, Novotny M, Hoksza D. PrankWeb: a web server for ligand binding site prediction and visualization. Nucleic Acids Res. 2019;47(W1):W345–W349. doi:10.1093/nar/gkz424.
42. Binkowski TA, Naghibzadeh S, Liang J. CASTp: Computed atlas of surface topography of proteins. Nucleic Acids Res. 2003;31(13):3352–3355. doi:10.1093/nar/gkg512.
43. Ayaz E, Alpsoy HC. garlic (Allium sativum) and traditional medicine. Turkiye Parazitolojii Dergisi. 2007;31(2):145–149.
44. Tesfaye A. Revealing the therapeutic uses of garlic (Allium sativum) and its potential for drug discovery. Sci World J. 2021;2021(1):8817288. doi:10.1155/2021/8817288.
45. Shang A, Cao SY, Xu XY, Gan RY, Tang GY, Corke H, Mavumengwana V, Li HB. Bioactive compounds and biological functions of garlic (Allium sativum L.) Foods. 2019;8(7):246. doi:10.3390/foods8070246.
46. Bayan L, Koulivand PH, Gorji A. Garlic: a review of potential therapeutic effects. Avicenna J Phytomed. 2014;4(1):1–14.
47. Batiha GES, Beshbishy AM, Wasef LG, Elewa YHA, Al-Sagan AA, El-Hack MEA, Taha AE, et al. Chemical constituents and pharmacological activities of garlic (Allium sativum L.): A review. Nutrients. 2020;12(3):872. doi:10.3390/nu12030872.
48. Iciek M, Kwiecień I, Chwatko G, Sokołowska-Jeżewicz M, Kowalczyk-Pachel D, Rokita H. The effects of garlic-derived sulfur compounds on cell proliferation, caspase 3 activity, thiol levels and anaerobic sulfur metabolism in human hepatoblastoma HepG2 cells. Cell Biochem Funct. 2012;30(3):198–204. doi:10.1002/cbf.1835.
49. Diantini A, Subarnas A, Lestari K, Halimah E, Susilawati Y, Supriyatna, Julaeha E, Achmad TH, Suradji EW, Yamazaki C, Kobayashi K, Koyama H, Abdulah R. Kaempferol-3-O-rhamnoside isolated from the leaves of Schima wallichii Korth. inhibits MCF-7 breast cancer cell proliferation through activation of the caspase cascade pathway. Oncol Lett. 2003;3(5):1069–1072. doi:10.3892/ol.2012.596.
50. Tsiklauri L, An G, Ruszaj DM, Alaniya M, Kemertelidze E, Morris ME. Simultaneous determination of the flavonoids robinin and kaempferol in human breast cancer cells by liquid chromatography-tandem mass spectrometry. J Pharm Biomed Anal. 2011;55(1):109–113. doi:10.1016/j.jpba.2010.12.021.
51. Yi X, Zuo J, Tan C, Xian S, Luo C, Chen S, Yu L, Luo Y. Kaempferol, a flavonoid compound from Gynura Medica induced apoptosis and growth inhibition in Mcf-7 breast cancer cell. Afr J Tradit Complement Altern Med. 2016;13(4):210–215. doi:10.21010/ajtcam.v13i4.27.
52. Roy N, Davis S, Narayanankutty A, Nazeem PA, Babu TD, Abida PS, Raghavamenon A. Garlic phytocompounds possess anticancer activity by specifically targeting breast cancer biomarkers-an in-silico study. Asian Pac J Cancer Prev. 2016;17(6):2883–2888. doi:APJCP.2016.17.6.2883.
53. Odubela OO, Omirin ES, Olanrewaju AJ, Olugbogi EA, Aribisala PO, Nwachukwu KC, Okoh EF, Blessed SN, Boboye SO. Identification of antagonists of pro-survival Bcl-2 from Morus alba in human malignancies: An in-silico approach. Scicom J Med Appl Med Sci. 2024;3(1):36–44. doi:10.54117/sjmams.v3i1.15.
54. Pan Y, Zheng YM, Ho WS. Effect of quercetin glucosides from Allium extracts on HepG2, PC-3 and HT-29 cancer cell lines. Oncol Lett. 2018;15(4):4657–4661. doi:10.3892/ol.2018.7893.
55. Ward AB, Mir H, Kapur N, Gales DN, Carriere PP, Singh S. Quercetin inhibits prostate cancer by attenuating cell survival and inhibiting anti-apoptotic pathways. World J Surg Oncol. 2018;16(1). doi:10.1186/s12957-018-1400-z.
56. Nam JS, Sharma A, Nguyen L, Chakraborty C, Sharma G, Lee SS. Application of bioactive quercetin in oncotherapy: From nutrition to nanomedicine. Mol. 2016;21(1):108. doi:10.3390/
molecules21010108.
57. Liu S, Matsuo T, Miyaji M, Hosoya O. Key pathways and genes influenced by a drug, NK-4, in human neurons. Invest Ophthalmol Vis Sci. 2018;59(9):6051.
58. Khan I, Bahuguna A, Kumar P, Bajpai VK, Kang SC. In vitro and in vivo antitumor potential of carvacrol nanoemulsion against human lung adenocarcinoma A549 cells via mitochondrial mediated apoptosis. Sci Rep. 2018;8(1). doi:10.1038/s41598-017-18644-9.
59. Imran M, Aslam M, Alsagaby SA, Saeed F, Ahmad I, Afzaal M, Arshad MU, Abdelgawad MA, El-Ghorab AH, Khames A, Shariati MA, Ahmad A, Hussain M, Imran A, Islam S. Therapeutic application of carvacrol: A comprehensive review. Food Sci Nutr. 2022;10(11):3544–3561. doi:10.1002/fsn3.2994.
60. Fatima K, Luqman S, Meena A. Carvacrol arrests the proliferation of hypopharyngeal carcinoma cells by suppressing ornithine decarboxylase and hyaluronidase activities. Front Nutr. 2022;9:857256. doi:10.3389/fnut.2022.857256.
61. Herrera-Calderon O, Yepes-Pérez AF, Quintero-Saumeth J, Rojas-Armas JP, Palomino-Pacheco M, Ortiz-Sánchez JM, Andía-Ayme V. Carvacrol: An in silico approach of a candidate drug on HER2, PI3Kα, mTOR, hER-α, PR, and EGFR receptors in the breast cancer. Evid Based Complement Alternat Med. 2020;1–12. doi:10.1155/2020/8830665.
62. Zari AT, Zari TA, Hakeem KR. Anticancer properties of eugenol: A review. Mol. 2021;26(23):7407. doi:10.3390/molecules26237407.
63. Yoo CB, Han KT, Cho KS, Ha J, Park HJ, Nam JH, Lee KT. Eugenol isolated from the essential oil of Eugenia caryophyllata induces a reactive oxygen species-mediated apoptosis in HL-60 human promyelocytic leukemia cells. Cancer Lett. 2005;225(1):41–52. doi:10.1016/j.canlet.2004.11.018.
64. Nazreen S, Elbehairi SEI, Malebari AM, Alghamdi N, Alshehri RF, Shati AA, Ali NM, Alfaifi MY, Elhenawy AA, Alam MM. New natural eugenol derivatives as antiproliferative agents: Synthesis, biological evaluation, and computational studies. ACS Omega. 2023;8(21):18811–18822. doi:10.1021/acsomega.3c00933.

Regular Issue Subscription Original Research
Volume 13
Issue 02
Received 17/09/2024
Accepted 27/10/2024
Published 04/11/2024
288

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