Virtual Screening and Elucidation of Putative Binding Mode for Small Molecule Antagonist of BCL2-BH4 Domain

Authors

  • Ireoluwa Y. Joel Department of Biochemistry, University of Ilorin, Ilorin Kwara state, Nigeria Author
  • Lateef A. Sulaimon Directorates of Chemical Sciences, Crescent University Abeokuta, Ogun State, Nigeria Author
  • Temidayo O. Adigun 1. Department of Biochemistry, University of Ilorin, Ilorin Kwara state, Nigeria Author
  • Ahmeedah O. Ajibola 1. Department of Biochemistry, University of Ilorin, Ilorin Kwara state, Nigeria Author
  • Olukayode O. Bankole Department of Science Laboratory Technology, School of Pure & Applied Sciences, Federal Polytechnic Ilaro, Ogun state, Nigeria Author https://orcid.org/0000-0001-8318-5431
  • Ugochukwu O. Ozojiofor Department of Biotechnology, Nigerian Defence Academy, Kaduna, Kaduna State, Nigeria Author
  • Ifelolu A. Remi-Esan Department of Science Laboratory Technology, School of Pure & Applied Sciences, Federal Polytechnic Ilaro, Ogun state, Nigeria Author
  • Abosede Ajibare 5. Department of Biochemistry, Faculty of Basic Medical Sciences, College of Medicine, University of Lagos Author https://orcid.org/0000-0002-6089-1760
  • Aishat A. Whyte Directorates of Chemical Sciences, Crescent University Abeokuta, Ogun State, Nigeria Author
  • Oluwaseun O. Taofeek Directorates of Chemical Sciences, Crescent University Abeokuta, Ogun State, Nigeria Author
  • Yusuf Salami Directorates of Chemical Sciences, Crescent University Abeokuta, Ogun State, Nigeria Author
  • Abosede C. Ajibare Department of Biochemistry, Faculty of Basic Medical Sciences, College of Medicine, University of Lagos, Nigeria Author https://orcid.org/0000-0002-5530-6205

DOI:

https://doi.org/10.4314/njbmb.v40i1.7

Keywords:

Molecular Dynamic Simulations, BCL-2 Antagonist, Apoptosis, Cancer, Computer-Aided Drug Design, BH4 Domain of BCL-2

Abstract

Cancer cells commonly evade apoptosis, making programmed cell death a key target in therapeutic development. Central to this process is the BCL2 protein family, with the BH4 domain of BCL2 identified as critical for anti-apoptotic function. To date, Lig-BDA366 is the only known molecule that binds this domain. Seeking to discover novel BH4-binding candidates, a virtual screening of approximately one million compounds yielded 11 promising small molecules, showing binding affinities between -84 and -64 kcal/mol. Advanced computational methods—including QM-polarized docking, Induced-fit docking, and QM-MM optimization—revealed probable binding modes for the top three ligands. Lig-139068 formed interactions with GLU13, MET16, LYS17, ASP31, and GLU42; Lig-138967 interacted with ASP10, ARG12, GLU13, HIS20, MET16, and GLU42; while Lig-38831 engaged ASP10, ARG12, GLU13, LYS17, and GLU42. These molecular interactions help explain their affinity for the BH4 domain. Molecular dynamics simulations confirmed stable binding of all three ligands, although Lig-38831 showed greater flexibility than Lig-BDA366. Density Functional Theory (DFT) analysis indicated that electrophilic mechanisms may underlie the reactivity of the ligands. Altogether, these computational insights support the potential of Lig-139068, Lig-138967, and Lig-38831 as candidates for further exploration in cancer therapeutics targeting the BH4 domain

Downloads

Download data is not yet available.

References

Ahmed, M., Maldonado, A. M., & Durrant, J. D. (2023). From byte to bench to bedside: Molecular dynamics simulations and drug discovery. BMC Biology, 21(1), 299. https://doi.org/10.1186/s12915-023-01791-z

Berry, M., Fielding, B., & Gamieldien, J. (2015). Practical considerations in virtual screening and molecular docking. In Emerging trends in computational biology, bioinformatics, and systems biology (pp. 487–502). https://doi.org/10.1016/B978-0-12-802508-6.00027-2

Bochevarov, A. D., Harder, E., Hughes, T. F., Greenwood, J. R., Braden, D. A., Philipp, D. M., ... & Friesner, R. A. (2013). Jaguar: A high-performance quantum chemistry software program with strengths in life and materials sciences. International Journal of Quantum Chemistry, 113(18), 2110–2142. https://doi.org/10.1002/qua.24481

Bowers, K. J., Chow, E., Xu, H., Dror, R. O., Eastwood, M. P., Gregersen, B. A., ... & Shaw, D. E. (2006). Scalable algorithms for molecular dynamics simulations on commodity clusters. In Proceedings of the ACM/IEEE Conference on Supercomputing (SC06), Tampa, Florida, November 11–17.

Brahmer, J., Reckamp, K. L., Baas, P., Crinò, L., Eberhardt, W. E. E., Poddubskaya, E., ... & Mitchell, P. L. (2015). Nivolumab versus docetaxel in advanced squamous-cell non-small-cell lung cancer. New England Journal of Medicine, 373, 123–135. https://doi.org/10.1056/NEJMoa1504627

Carrizosa, D. R., & Gold, K. A. (2015). New strategies in immunotherapy for non-small cell lung cancer. Translational Lung Cancer Research, 4(5), 553–559. https://doi.org/10.3978/j.issn.2218-6751.2015.06.05

Chevillard, F., & Kolb, P. (2015). SCUBIDOO: A large yet screenable and easily searchable database of computationally created chemical compounds optimized toward high likelihood of synthetic tractability. Journal of Chemical Information and Modeling, 55(9), 1824–1835. https://doi.org/10.1021/acs.jcim.5b00203

De Vivo, M., Masetti, M., Bottegoni, G., & Cavalli, A. (2016). Role of Molecular Dynamics and Related Methods in Drug Discovery. Journal of Medicinal Chemistry, 59(9), 4035–4061. https://doi.org/10.1021/acs.jmedchem.5b01684

Duay, S. S., Yap, R. C. Y., Gaitano, A. L. 3rd, Santos, J. A. A., & Macalino, S. J. Y. (2023). Roles of virtual screening and molecular dynamics simulations in discovering and understanding antimalarial drugs. International Journal of Molecular Sciences, 24(11), 9289. https://doi.org/10.3390/ijms24119289

Gupta, V. P. (2016). Density functional theory (DFT) and time dependent DFT (TDDFT). In Density functional theory (pp. 1–20). https://doi.org/10.1016/B978-0-12-803478-1.00005-4

Haggarty, S. J., Koeller, K. M., Wong, J. C., Grozinger, C. M., & Schreiber, S. L. (2003). Domain-selective small-molecule inhibitor of histone deacetylase 6 (HDAC6)-mediated tubulin deacetylation. Proceedings of the National Academy of Sciences, 100(8), 4389–4394. https://doi.org/10.1073/pnas.0430973100

Halgren, T. A., Murphy, R. B., Friesner, R. A., Beard, H. S., Frye, L. L., Pollard, W. T., ... & Shenkin, P. S. (2004). Glide: A new approach for rapid, accurate docking and scoring. 2. Enrichment factors in database screening. Journal of Medicinal Chemistry, 47(7), 1750–1759. https://doi.org/10.1021/jm030644s

Han, B., Park, D., Li, R., Xie, M., Owonikoko, T. K., Zhang, G., ... & Deng, X. (2015). Small-molecule Bcl2 BH4 antagonist for lung cancer therapy. Cancer Cell, 27(6), 852–863. https://doi.org/10.1016/j.ccell.2015.04.010

Harder, E., Damm, W., Maple, J., Wu, C., Reboul, M., Xiang, J. Y., ... & Friesner, R. A. (2015). OPLS3: A force field providing broad coverage of drug-like small molecules and proteins. Journal of Chemical Theory and Computation, 12(1), 281–296. https://doi.org/10.1021/acs.jctc.5b00864

Hirotani, M., Zhang, Y., Fujita, N., Naito, M., & Tsuruo, T. (1999). NH2-terminal BH4 domain of Bcl-2 is functional for heterodimerization with Bax and inhibition of apoptosis. Journal of Biological Chemistry, 274(29), 20415–20420. https://doi.org/10.1074/jbc.274.29.20415

Hollingsworth, S. A., & Dror, R. O. (2018). Molecular dynamics simulation for all. Neuron, 99(6), 1129–1143. https://doi.org/10.1016/j.neuron.2018.08.011

Hu, Y., Zhou, L., Zhu, X., Dai, D., Bao, Y., & Qiu, Y. (2018). Pharmacophore modeling, multiple docking, and molecular dynamics studies on Wee1 kinase inhibitors. Journal of Biomolecular Structure & Dynamics, 36(13), 3467–3480. https://doi.org/10.1080/07391102.2018.1495576

Jacobson, M. P., Pincus, D. L., Rapp, C. S., Day, T. J., Honig, B., Shaw, D. E., & Friesner, R. A. (2004). A hierarchical approach to all-atom protein loop prediction. Proteins: Structure, Function, and Bioinformatics, 55(2), 351–367. https://doi.org/10.1002/prot.10613

Kombo, D. C., Grinevich, V. P., Hauser, T. A., Sidach, S., & Bencherif, M. (2013). QM-polarized ligand docking accurately predicts the trend in binding affinity of a series of arylmethylene quinuclidine-like derivatives at the α4β2 and α3β4 nicotinic acetylcholine receptors (nAChRs). Bioorganic & Medicinal Chemistry Letters, 23(17), 4842–4847. https://doi.org/10.1016/j.bmcl.2013.06.094

Kump, K. J., Miao, L., Mady, A. S. A., Ansari, N. H., Shrestha, U. K., Yang, Y., ... & Chen, J. L. (2020). Discovery and characterization of 2,5-substituted benzoic acid dual inhibitors of the anti-apoptotic Mcl-1 and Bfl-1 proteins. Journal of Medicinal Chemistry, 63(5), 2489–2510. https://doi.org/10.1021/acs.jmedchem.9b01442

Lionta, E., Spyrou, G., Vassilatis, D. K., & Cournia, Z. (2014). Structure-based virtual screening for drug discovery: Principles, applications and recent advances. Current Topics in Medicinal Chemistry, 14(16), 1923–1938. https://doi.org/10.2174/1568026614666140929124445

Liu, Z., Wild, C., Ding, Y., Ye, N., Chen, H., Wold, E. A., ... & Ding, C. (2016). BH4 domain of Bcl-2 as a novel target for cancer therapy. Drug Discovery Today, 21(6), 989–996. https://doi.org/10.1016/j.drudis.2015.11.008

López-Blanco, J. R., Aliaga, J. I., Quintana-Ortí, E. S., & Chacón, P. (2014). IMODS: Internal coordinates normal mode analysis server. Nucleic Acids Research, 42(W1), W271–W276. https://doi.org/10.1093/nar/gku339

Mangat, H. K., Rani, M., Pathak, R. K., & Chhuneja, P. (2022). Virtual screening, molecular dynamics, and binding energy-MM-PBSA studies of natural compounds to identify potential EcR inhibitors against Bemisia tabaci Gennadius. PLOS ONE, 17(1), e0261545. https://doi.org/10.1371/journal.pone.0261545

Martín-Acosta, P., & Xiao, X. (2021). PROTACs to address the challenges facing small molecule inhibitors. European Journal of Medicinal Chemistry, 210, 112993. https://doi.org/10.1016/j.ejmech.2020

Mohammadi, M. K., Firuzi, O., Khoshneviszadeh, M. R., Razzaghi-Asl, N., Sepehri, S., & Miri, R. (2014). Derivatives: Synthesis, cytotoxic activity and molecular docking studies on B-cell lymphoma 2. Journal of Pharmaceutical Sciences, 2014, 1–11. https://doi.org/10.1155/2014/879308

Monaco, G., Decrock, E., Akl, H., Ponsaerts, R., Vervliet, T., Luyten, T., ... & Bultynck, G. (2012). Selective regulation of IP3-receptor-mediated Ca2+ signaling and apoptosis by the BH4 domain of Bcl-2 versus Bcl-Xl. Cell Death and Differentiation, 19(2), 295–309. https://doi.org/10.1038/cdd.2011.92

Parr, R. G., Szentpály, L. V., & Liu, S. (1999). Electrophilicity index. Journal of the American Chemical Society, 121(9), 1922–1924. https://doi.org/10.1021/ja983494x

Pavitha, P., Prashanth, J., Ramu, G., Ramesh, G., Mamatha, K., & Reddy, B. S. V. (2017). Synthesis, structural, spectroscopic, anti-cancer and molecular docking studies on novel 2-[(anthracene-9-ylmethylene) amino]-2-methylpropane-1,3-diol using XRD, FTIR, NMR, UV–Vis spectra and DFT. Journal of Molecular Structure, 1147, 406–426. https://doi.org/10.1016/j.molstruc.2017.06.095

Perini, G. F., Ribeiro, G. N., Pinto Neto, J. V., & Ribeiro, V. P. (2018). BCL-2 as a therapeutic target for hematological malignancies. Journal of Hematology & Oncology, 11, 65. https://doi.org/10.1186/s13045-018-0608-2

Qian, S., Wei, Z., Yang, W., Huang, J., Yang, Y., & Wang, J. (2022). The role of BCL-2 family proteins in regulating apoptosis and cancer therapy. Frontiers in Oncology, 12, 985363. https://doi.org/10.3389/fonc.2022.985363

Radha, G., & Raghavan, S. C. (2017). BCL2: A promising cancer therapeutic target. Biochimica et Biophysica Acta - Reviews on Cancer, 1868(2), 309–314. https://doi.org/10.1016/j.bbcan.2017.06.004

Reed, J. C. (2002). Apoptosis-based therapies. Nature Reviews Drug Discovery, 1(2), 111–121. https://doi.org/10.1038/nrd726

Rong, Y. P., Barr, P., Yee, V. C., & Distelhorst, C. W. (2009a). Targeting Bcl-2 based on the interaction of its BH4 domain with the inositol 1,4,5-trisphosphate receptor. Biochimica et Biophysica Acta - Molecular Cell Research, 1793(6), 971–978. https://doi.org/10.1016/j.bbamcr.2008.10.015

Rong, Y. P., Bultynck, G., Aromolaran, A. S., Zhong, F., Parys, J. B., De Smedt, H., ... & Distelhorst, C. W. (2009b). The BH4 domain of Bcl-2 inhibits ER calcium release and apoptosis by binding the regulatory and coupling domain of the IP3 receptor. Proceedings of the National Academy of Sciences, 106(34), 14397–14402. https://doi.org/10.1073/pnas.0907555106

Salo-Ahen, O. M. H., Alanko, I., Bhadane, R., & Lahtela-Kakkonen, M. (2021). Molecular dynamics simulations in drug discovery and pharmaceutical development. Processes, 9(1), 71. https://doi.org/10.3390/pr9010071

Sastry, G. M., Adzhigirey, M., Day, T., Annabhimoju, R., & Sherman, W. (2013). Protein and ligand preparation: Parameters, protocols, and influence on virtual screening enrichments. Journal of Computer-Aided Molecular Design, 27(3), 221–234. https://doi.org/10.1007/s10822-013-9644-8

Schrödinger LLC. (2020). Maestro (Release 2020-3).

Schrödinger LLC. (2021). Maestro (Release 2022-3). https://www.schrodinger.com/products/maestro

Shelley, J. C., Cholleti, A., Frye, L. L., Greenwood, J. R., Timlin, M. R., & Uchimaya, M. (2007). Epik: A software program for pKa prediction and protonation state generation for drug-like molecules. Journal of Computer-Aided Molecular Design, 21(12), 681–691. https://doi.org/10.1007/s10822-007-9133-z

Sherman, W., Day, T., Jacobson, M. P., Friesner, R. A., & Farid, R. (2006). Novel procedure for modeling ligand/receptor induced fit effects. Journal of Medicinal Chemistry, 49(2), 534–553. https://doi.org/10.1021/jm050540c

Singh, N., Villoutreix, B. O., & Ecker, G. F. (2019). Rigorous sampling of docking poses unveils binding hypothesis for the halogenated ligands of L-type amino acid transporter 1 (LAT1). Scientific Reports, 9, 1–20. https://doi.org/10.1038/s41598-019-51455-8

Townsend, P. A., Kozhevnikova, M. V., Cexus, O. N. F., & Shamsuddin, S. (2021). BH3-mimetics: Recent developments in cancer therapy. Journal of Experimental & Clinical Cancer Research, 40, 355. https://doi.org/10.1186/s13046-021-02157-5

Wang, L., Xiang, S., Williams, K. A., Dong, H., Bai, W., Nicosia, S. V., & Khochbin, S. (2012). Depletion of HDAC6 enhances cisplatin-induced DNA damage and apoptosis in non-small cell lung cancer cells. PLoS ONE, 7(5), e42813. https://doi.org/10.1371/journal.pone.0042813

Yang, T. M., Barbone, D., & Broaddus, V. C. (2009). Bortezomib-induced apoptosis in the treatment of non-small cell lung cancer. Journal of Internal Medicine Taiwan, 20, 106–119. https://doi.org/10.6314/JIMT.2009.20(2).02

Additional Files

Published

2025-10-31

Data Availability Statement

Data are all contained within the paper. All data presented in this article are available with the authors. The request on the data should be directed to the corresponding author on: adlat4best@yahoo.com or lateef.sulaimon@cuab.edu.ng

Issue

Vol. 40 No. 1: January - March, 2025

Section

Research Articles

Categories

License

Copyright (c) 2025 Ireoluwa Y. Joel, Lateef A. Sulaimon, Temidayo O. Adigun, Ahmeedah O. Ajibola, Olukayode O. Bankole, Ugochukwu O. Ozojiofor, Ifelolu A. Remi-Esan, Abosede Ajibare, Aishat A. Whyte, Oluwaseun O. Taofeek, Yusuf Salami, Abosede C. Ajibare (Author)

Creative Commons License

This work is licensed under a Creative Commons Attribution 4.0 International License.

How to Cite

Virtual Screening and Elucidation of Putative Binding Mode for Small Molecule Antagonist of BCL2-BH4 Domain. (2025). Nigerian Journal of Biochemistry and Molecular Biology, 40(1), 48-58. https://doi.org/10.4314/njbmb.v40i1.7