Skip to main content Skip to main navigation menu Skip to site footer

Molecular docking studies of Brucein D as a potential inhibitor of the Bcl-2 anti-apoptotic protein

  • Pandu Ishaq Nandana ,
  • Haerani Rasyid ,
  • Prihantono ,
  • Ika Yustisia ,
  • Lukman Hakim ,


Abstract

Link of Video Abstract: https://youtu.be/JOzTSty10v4

Background: Brucein D (BrD), a quassinoid isolated from Brucea javanica fruit, reportedly demonstrates anti-tumor activity. Bcl-2 is an anti-apoptotic protein that inhibits apoptosis and leads to cancer progression. This study aims to evaluate the inhibitory effect of BrD against the anti-apoptotic protein Bcl-2 by molecular docking study.

Methods: We investigated the activity of BrD against Bcl-2 through molecular docking in silico compared to the chemotherapeutic drugs doxorubicin and docetaxel. Molecular docking analysis was conducted using the Lipinski rule of five drug-likeness analyses, PASS Online prediction, PyRx v0.8, Discovery Studio DS BIOVIA 2016 v16, and PyMol v2.4.

Results: Current results show that BrD is qualified as a drug and can pass cell membranes without toxicity. The PASS prediction also shows that BrD can be activated as an anti-neoplastic inside the human body with Pa higher than Pi. BrD can make a constant and stable bond to Bcl-2 with a binding energy of -8.3 kcal/mol, almost equal to doxorubicin and docetaxel. BrD can form six types of hydrogen bonds that show stability to temperature and pressure.

Conclusion: BrD has shown to be a promising alternative for an anti-cancer drug by inhibiting the Bcl-2 anti-apoptotic protein with low toxicity in normal cells.

Keywords: anti-cancer Bcl-2 Brucein D molecular docking

References

  1. Global Burden of Disease 2019 Cancer Collaboration, Kocarnik JM, Compton K, Dean FE, Fu W, Gaw BL, et al. Cancer Incidence, Mortality, Years of Life Lost, Years Lived With Disability, and Disability-Adjusted Life Years for 29 Cancer Groups From 2010 to 2019: A Systematic Analysis for the Global Burden of Disease Study 2019. JAMA Oncol. 2022;8(3):420-444.
  2. Prihantono, Faruk M. Breast cancer resistance to chemotherapy: When should we suspect it and how can we prevent it?. Ann Med Surg (Lond). 2021;70:102793.
  3. Bukowski K, Kciuk M, Kontek R. Mechanisms of Multidrug Resistance in Cancer Chemotherapy. Int J Mol Sci. 2020;21(9):3233.
  4. Kerr JF, Wyllie AH, Currie AR. Apoptosis: a basic biological phenomenon with wide-ranging implications in tissue kinetics. Br J Cancer. 1972;26(4):239-257.
  5. Pobor G, Pettersson S, Bandeira A, Martinez-A C, Coutinho A. B lymphocyte activation upon exclusive recognition of major histocompatibility antigens by T helper cells. Eur J Immunol. 1984;14(3):222-227.
  6. Perini GF, Ribeiro GN, Pinto Neto JV, Campos LT, Hamerschlak N. BCL-2 as therapeutic target for hematological malignancies. J Hematol Oncol. 2018;11(1):65.
  7. Subeki, Matsuura H, Takahashi K, Nabeta K, Yamasaki M, Maede Y, et al. Screening of Indonesian medicinal plant extracts for antibabesial activity and isolation of new quassinoids from Brucea javanica. J Nat Prod. 2007;70(10):1654-1657.
  8. Chen M, Chen R, Wang S, Tan W, Hu Y, Peng X, et al. Chemical components, pharmacological properties, and nanoparticulate delivery systems of Brucea javanica. Int J Nanomedicine. 2013;8:85-92.
  9. Bagheri E, Hajiaghaalipour F, Nyamathulla S, Salehen N. The apoptotic effects of Brucea javanica fruit extract against HT29 cells associated with p53 upregulation and inhibition of NF-κB translocation. Drug Des Devel Ther. 2018;12:657-671.
  10. Subeki, Muhartono. Senyawa Brusein-A dari Buah Makasar (Brucea javanica (L.) Merr.) sebagai Antiproliferasi terhadap Sel Kanker Payudara T47D. Majalah Kedokteran Bandung. 2015;47(1):22–28.
  11. Sutejo IR, Putri H, Handayani S, Jenie RI, Meiyanto E. In Vitro Study of the Combination of Doxorubicin, Curcuma xanthorrhiza, Brucea javanica, and Ficus septica as a Potential Novel Therapy for Metastatic Breast Cancer. Indonesia Journal of Pharmacy. 2019;30(1):15-24.
  12. Lai ZQ, Ip SP, Liao HJ, Lu Z, Xie JH, Su ZR, Chen YL, et al. Brucein D, a Naturally Occurring Tetracyclic Triterpene Quassinoid, Induces Apoptosis in Pancreatic Cancer through ROS-Associated PI3K/Akt Signaling Pathway. Front Pharmacol. 2017;8:936.
  13. Tan B, Huang Y, Lan L, Zhang B, Ye L, Yan W, et al. Bruceine D induces apoptosis in human non-small cell lung cancer cells through regulating JNK pathway. Biomed Pharmacother. 2019;117:109089.
  14. Luo C, Wang Y, Wei C, Chen Y, Ji Z. The anti-migration and anti-invasion effects of Bruceine D in human triple-negative breast cancer MDA-MB-231 cells. Exp Ther Med. 2020;19(1):273-279.
  15. Khaerunnisa S, Suhartarti, Awaluddin R. Penelitian In Silico Untuk Pemula. Airlangga University Press: Surabaya. 2020.
  16. Arnott JA, Planey SL. The influence of lipophilicity in drug discovery and design. Expert Opin Drug Discov. 2012;7(10):863-875.
  17. Ramírez D, Caballero J. Is It Reliable to Use Common Molecular Docking Methods for Comparing the Binding Affinities of Enantiomer Pairs for Their Protein Target?. Int J Mol Sci. 2016;17(4):525.
  18. Ferreira de Freitas R, Schapira M. A systematic analysis of atomic protein-ligand interactions in the PDB. Medchemcomm. 2017;8(10):1970-1981.
  19. Lipinski CA. Lead- and drug-like compounds: the rule-of-five revolution. Drug Discov Today Technol. 2004;1(4):337-341.
  20. Hassan NM, Alhossary AA, Mu Y, Kwoh CK. Protein-Ligand Blind Docking Using QuickVina-W With Inter-Process Spatio-Temporal Integration. Sci Rep. 2017;7(1):15451.
  21. Tacar O, Sriamornsak P, Dass CR. Doxorubicin: an update on anticancer molecular action, toxicity and novel drug delivery systems. J Pharm Pharmacol. 2013;65(2):157-170.
  22. Albany C, Sonpavde G. Docetaxel for the treatment of bladder cancer. Expert Opin Investig Drugs. 2015;24(12):1657-1664.
  23. Vela L, Marzo I. Bcl-2 family of proteins as drug targets for cancer chemotherapy: the long way of BH3 mimetics from bench to bedside. Curr Opin Pharmacol. 2015;23:74-81.
  24. Kusuma SMW, Utomo DH, Susanti R, Molecular Mechanism of Inhibition of Cell Proliferation: An In Silico Study of the Active Compounds in Curcuma longa as an Anticancer. J Trop Biodivers Biotechnol. 2022;7(3):1-16.
  25. Almansour NM, Allemailem KS, Abd El Aty AA, Ismail EIF, Ibrahim MAA. In Silico Mining of Natural Products Atlas (NPAtlas) Database for Identifying Effective Bcl-2 Inhibitors: Molecular Docking, Molecular Dynamics, and Pharmacokinetics Characteristics. Molecules. 2023;28(2):783.
  26. Suparman DD, Yustisia I, Arsyad A, Natsir R, Cangara MH, Patellongi I. Studi In Silico Potensi Anti Kanker Senyawa Turunan Kumarin Terhadap Protein Bcl-2. Majalah Farmasi dan Farmakologi. 2021;25(2):84-87.
  27. Wulanawati A, Noviardi H, Ibrohim MSM. Finding a Potential Bruceine D Inhibitor for Apoptotic Resistance Protein Pancreatic Cancer Based on Molecular Docking, Indonesian Journal of Chemistry. 2018;18(3):566-572.
  28. Ananto AD, Muliasari H, Hamdin CD. Studi In Silico Bioaktivitas Antikanker Senyawa Aktif Dalam Minyak Biji Buah Wali [Brucea javanica (L.) Merr]. Sasambo Journal of Pharmacy. 2020;1(2):26–29.
  29. Artini IGA, Astuti KW, Trapika IGMGSC, Indrayani AW. The bcl-2 and caspase-3 expression after purple sweet potato treatment on isoniazid and rifampicin-induced liver injury. Bali Medical Journal. 2023;12(2):1204-1210.
  30. Suzy-Indharty R. Increase Of Serum Bcl-2 Concentration In Severe Head Injury: The Role of ACTH4-10Pro8Gly9Pro10 and HMG Co-A Reductase Inhibitor. Bali Medical Journal. 2013;2(1):21-26.
  31. Ovaditya SZ, Briliantika SP, Chodidjah, Sumarawati T. The effect of Curcuma longa on fasting blood glucose, MMP-9 and IFN-γ in diabetes mellitus: an experimental study. Bali Medical Journal. 2022;11(3):1996-2002.

How to Cite

Nandana, P. I., Rasyid, H. ., Prihantono, Yustisia, I., & Hakim, L. . (2023). Molecular docking studies of Brucein D as a potential inhibitor of the Bcl-2 anti-apoptotic protein. Bali Medical Journal, 12(2), 2148–2152. https://doi.org/10.15562/bmj.v12i2.4414
ACM ACS APA ABNT Chicago Harvard IEEE MLA Turabian Vancouver
Download Citation
Endnote/Zotero/Mendeley (RIS) BibTeX

HTML
7

Total
6

Share