Computational Exploration of Betulinic Acid Hybrids as Dual BCL-2/BCL-XL Inhibitors

firstₚage Download PDF settings Order Article Reprints Font Type: Arial Georgia Verdana Font Size: Aa Aa Aa Line Spacing:    Column Width:    Background: Open AccessAbstract Computational Exploration of Betulinic Acid Hybrids as Dual BCL-2/BCL-XL Inhibitors † by Elisabeta P. AtyimElisabeta P. Atyim SciProfiles Scilit Preprints. org Google Scholar 1, 2, *, Marius MiocMarius Mioc SciProfiles Scilit Preprints. org Google Scholar 1, 2 and Codruța ȘoicaCodruța Șoica SciProfiles Scilit Preprints. org Google Scholar 1, 2 1 Faculty of Pharmacy, Victor Babes University of Medicine and Pharmacy, 300041 Timisoara, Romania 2 Research Center for Experimental Pharmacology and Drug Design, Victor Babes University of Medicine and Pharmacy, 300041 Timisoara, Romania * Author to whom correspondence should be addressed. † Presented at the International Conference on Interdisciplinary Approaches and Emerging Trends in Pharmaceutical Doctoral Research: Innovation and Integration, Timisoara, Romania, 7–9 July 2025. Proceedings 2025, 127 (1), 14; https: //doi. org/10. 3390/proceedings2025127014 Published: 25 September 2025 (This article belongs to the Proceedings of International Conference on Interdisciplinary Approaches and Emerging Trends in Pharmaceutical Doctoral Research: Innovation and Integration) Download keyboardₐrrowdown Download PDF Download PDF with Cover Download XML Download Epub Versions Notes Keywords: molecular docking; MD simulation; ADME/T property prediction; betulinic acid hybrids; Bcl-2 inhibitors Betulinic acid (BA), a lupane-type triterpene widely studied for its selective cytotoxicity against malignancies 1, shows synergistic pro-apoptotic activity when combined with blockade of anti-apoptotic B-cell lymphoma-2 (BCL-2) proteins, key targets of mitochondrial integrity in cancer cells 2. Guided by this rationale, we assembled a virtual library of BA hybrids by covalently linking the triterpene scaffold to natural molecules with reported antioxidant and anticancer activities. After physicochemical and drug-likeness filtering, the candidates were docked into the BH3-binding groove of BCL-2 (PDB ID: 4LVT), BCL-XL (PDB ID: 2YXJ), and the chimeric receptor BCL2-XL (PDB ID: 2W3L). Two hybrids, BA-Celastrol and BA-Proanthocyanidin B2, emerged with docking scores of −13. 0 kcal/mol and −12. 5 kcal/mol, respectively, against chimeric BCL2-XL (2W3L) ; −10. 7 and −10. 2 kcal/mol, respectively, against BCL-XL (2YXJ) ; and −9. 3 and −8. 7 kcal/mol, respectively, on BCL-2 (4LVT), outperforming the parent compound BA in each case. Molecular-mechanics/Poisson–Boltzmann surface area calculations and 100 ns molecular dynamics simulations confirmed stable complexes. In silico Absorption, Distribution, Metabolism, Excretion, and Toxicity (ADMET) profiling predicted favorable profiles for both compounds. Collectively, these findings highlight BA-Celastrol and BA-Proanthocyanidin B2 as a promising dual BCL-2/BCL-XL that can be further synthesized and biologically assessed for experimental validation. Author ContributionsConceptualization, M. M. and E. P. A. ; methodology, E. P. A. ; software, M. M. ; validation, M. M. , C. Ș. and E. P. A. ; formal analysis, M. M. ; investigation, E. P. A. ; resources, C. Ș. ; data curation, E. P. A. ; writing—original draft preparation, E. P. A. ; writing—review and editing, M. M. ; visualization, E. P. A. ; supervision, C. Ș. ; project administration, M. M. ; funding acquisition, M. M. All authors have read and agreed to the published version of the manuscript. FundingThis research received no external funding. Institutional Review Board StatementNot applicable. Informed Consent StatementNot applicable. Data Availability StatementThe original contributions presented in the study are included in the manuscript, further inquiries can be directed to the corresponding author. Conflicts of InterestThe authors declare no conflict of interest. ReferencesWang, K. ; Shang, J. ; Tao, C. ; Huang, M. ; Wei, D. ; Yang, L. ; Yang, J. ; Fan, Q. ; Ding, Q. ; Zhou, M. Advancements in betulinic acid-loaded nanoformulations for enhanced anti-tumor therapy. Int. J. Nanomed. 2024, 19, 14075–14103. Google Scholar CrossRef PubMedCroce, C. M. ; Vaux, D. ; Strasser, A. ; Opferman, J. T. ; Czabotar, P. E. ; Fesik, S. W. The BCL-2 protein family: From discovery to drug development. Cell Death Differ. 2025, 32, 1369–1381. Google Scholar CrossRef PubMedDisclaimer/Publisher's Note: The statements, opinions and data contained in all publications are solely those of the individual author (s) and contributor (s) and not of MDPI and/or the editor (s). MDPI and/or the editor (s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content. © 2025 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https: //creativecommons. org/licenses/by/4. 0/). Share and Cite MDPI and ACS Style Atyim, E. P. ; Mioc, M. ; Șoica, C. Computational Exploration of Betulinic Acid Hybrids as Dual BCL-2/BCL-XL Inhibitors. Proceedings 2025, 127, 14. https: //doi. org/10. 3390/proceedings2025127014 AMA Style Atyim EP, Mioc M, Șoica C. Computational Exploration of Betulinic Acid Hybrids as Dual BCL-2/BCL-XL Inhibitors. Proceedings. 2025; 127 (1): 14. https: //doi. org/10. 3390/proceedings2025127014 Chicago/Turabian Style Atyim, Elisabeta P. , Marius Mioc, and Codruța Șoica. 2025. "Computational Exploration of Betulinic Acid Hybrids as Dual BCL-2/BCL-XL Inhibitors" Proceedings 127, no. 1: 14. https: //doi. org/10. 3390/proceedings2025127014 APA Style Atyim, E. P. , Mioc, M. , & Șoica, C. (2025). Computational Exploration of Betulinic Acid Hybrids as Dual BCL-2/BCL-XL Inhibitors. Proceedings, 127 (1), 14. https: //doi. org/10. 3390/proceedings2025127014 Article Metrics No No Article Access Statistics Multiple requests from the same IP address are counted as one view.