Structure-Based Computational Evaluation of Betulinic Acid-Derived Hybrids as Potential Bcl-2/Bcl-XL Modulators

The anti-apoptotic Bcl-2 protein family, frequently upregulated in a wide range of cancers, contributes to tumor persistence and therapeutic resistance, making these proteins attractive targets for structure-based inhibitor development. Betulinic acid-derived hybrids represent promising scaffolds for apoptosis-oriented anticancer drug discovery due to their reported antiproliferative and pro-apoptotic properties. In this study, a virtual library of 152 betulinic acid-derived hybrids was screened against Bcl-2 and Bcl-XL. This molecular docking study using AutoDock Vina identified BA–Celastrol and BA–Proanthocyanidin B2 as top-ranked ligands, with docking scores ranging from −13.00 to −8.7 kcal/mol. Both compounds were further analyzed by 100 ns molecular dynamics simulation runs, which revealed system-dependent ligand behavior rather than uniform preservation of the initial docked pose across all complexes. BA–Celastrol showed a more compact internal ligand conformation in the ligand property and RMSF analyses, whereas BA–Proanthocyanidin B2 showed greater intramolecular flexibility and conformational adaptability. Ligand displacement relative to the protein differed between targets, with BA–Proanthocyanidin B2 showing a more retained profile in the Bcl-XL model and BA–Celastrol showing more moderate positional behavior in the Bcl-2 model. MM-GBSA calculations resulted in free energy values ranging from −4.95 to −31.82 kcal/mol, indicating protein-dependent energetic differences across the investigated systems. Based on docking performance, molecular dynamics stability, and energetic data, both hybrids were ranked as computational candidates for further exploration against Bcl-2 family targets. The present findings, although confined to computational analysis, underscore the need for prioritizing betulinic acid-based hybrids for subsequent experimental evaluation.