Rational Design of Betulin-Based Hybrids as Multi-Target Inhibitors of Anti-Apoptotic BCL Proteins

first_page Download PDF settings Order Article Reprints Font Type: Arial Georgia Verdana Font Size: Aa Aa Aa Line Spacing:    Column Width:    Background: Open AccessAbstract Rational Design of Betulin-Based Hybrids as Multi-Target Inhibitors of Anti-Apoptotic BCL Proteins † by Mihaela ČobanMihaela Čoban SciProfiles Scilit Preprints.org Google Scholar 1,2,* and Marius MiocMarius Mioc SciProfiles Scilit Preprints.org Google Scholar 1,2 1 Faculty of Pharmacy, Victor Babes University of Medicine and Pharmacy, 300041 Timișoara, Romania 2 Research Center for Experimental Pharmacology and Drug Design, Victor Babes University of Medicine and Pharmacy, 300041 Timișoara, 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), 21; https://doi.org/10.3390/proceedings2025127021 Published: 28 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 keyboard_arrow_down Download PDF Download PDF with Cover Download XML Versions Notes Keywords: triterpenes; betulin derivatives; BCL-2 proteins; molecular docking; pro-apoptotic effects Triterpenes such as betulin are intensively studied for their intrinsic pro-apoptotic effects in cancer, providing a privileged scaffold for anti-tumor drug design [1,2]. As part of this study, we built a focused virtual library in which the 3β- and 28-hydroxyl groups of betulin were tethered via ω-chloro-alkyl linkers of variable length and then esterified with either hydroxybenzotriazole or 1,2,4-triazole-3-thiol and 1,3,4-oxadiazole-2-thiol fragments bearing diverse 5-substituted groups. Docking analysis against the anti-apoptotic proteins BCL-2 (PDB 4LVT), BCL-XL (2YXJ), and MCL-1 (5LOF) was carried out using both AutoDock Vina [3] and Glide scoring functions. Six independent rankings (3 targets × 2 scoring functions) were generated; compounds appearing in the top 20 (by binding score) of at least four lists were advanced. This consensus ranking yielded five hits: two hydroxybenzotriazole esters connected through two- and four-carbon spacers, two 5-(2-naphthyl)-1,3,4-oxadiazole-2-thiol esters with analogous spacers, and one 5-(4-chlorophenyl)-1,3,4-oxadiazole-2-thiol linked by a single-carbon bridge. All candidates underwent 100 ns molecular dynamics simulations in an explicit solvent with each protein partner. Root-mean-square deviation trajectories, hydrogen-bond occupancy, and MM/GBSA free-energy decomposition confirmed conformational stability and persistent anchoring within the BH3-binding grooves. Our results support the capacity of tailored betulin derivatives to engage multiple anti-apoptotic BCL family members, which is a strategy expected to circumvent resistance mediated by functional redundancy. The selected hybrids can then be synthesized and their pro-apoptotic activity validated in relevant cancer cell models. Author ContributionsConceptualization, M.Č. and M.M.; Methodology, M.M.; Software, M.M.; Investigation, M.Č.; Data Curation, M.Č.; Writing—Original Draft Preparation, M.Č.; Writing—Review and Editing, M.M.; Supervision, 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 authors.Conflicts of InterestThe authors declare no conflict of interest.ReferencesFulda, S. Betulinic Acid for cancer treatment and prevention. Int. J. Mol. Sci. 2008, 9, 1096–1107. [Google Scholar] [CrossRef] [PubMed]Lessene, G.; Czabotar, P.E.; Colman, P.M. BCL-2 family antagonists for cancer therapy. Nat. Rev. Drug Discov. 2008, 7, 989–1000. [Google Scholar] [CrossRef] [PubMed]Trott, O.; Olson, A.J. AutoDock Vina: Improving the speed and accuracy of docking with a new scoring function. J. Comput. Chem. 2010, 31, 455–461. [Google Scholar] [CrossRef] [PubMed]Disclaimer/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 Čoban, M.; Mioc, M. Rational Design of Betulin-Based Hybrids as Multi-Target Inhibitors of Anti-Apoptotic BCL Proteins. Proceedings 2025, 127, 21. https://doi.org/10.3390/proceedings2025127021 AMA Style Čoban M, Mioc M. Rational Design of Betulin-Based Hybrids as Multi-Target Inhibitors of Anti-Apoptotic BCL Proteins. Proceedings. 2025; 127(1):21. https://doi.org/10.3390/proceedings2025127021 Chicago/Turabian Style Čoban, Mihaela, and Marius Mioc. 2025. "Rational Design of Betulin-Based Hybrids as Multi-Target Inhibitors of Anti-Apoptotic BCL Proteins" Proceedings 127, no. 1: 21. https://doi.org/10.3390/proceedings2025127021 APA Style Čoban, M., & Mioc, M. (2025). Rational Design of Betulin-Based Hybrids as Multi-Target Inhibitors of Anti-Apoptotic BCL Proteins. Proceedings, 127(1), 21. https://doi.org/10.3390/proceedings2025127021 Article Metrics No No Article Access Statistics Multiple requests from the same IP address are counted as one view.