Targeting Anti-Apoptotic Bcl-2 Proteins with Triterpene-Heterocyclic Derivatives: A Combined Dual Docking and Molecular Dynamics Study

Anti-apoptotic Bcl-2 family proteins (Bcl-2, Bcl-xL, and Mcl-1), are often overexpressed in cancer, which aids tumor growth and treatment resistance. As a result, these proteins are excellent candidates for novel anticancer drugs. Within this study a virtual library of betuline derivatives was built and screened for possible Bcl-2, Bcl-XL, and Mcl-1 inhibitors. For every target, molecular docking simulations were performed using two different engines (AutoDock Vina and Glide). The ligands that most frequently appeared among the top candidates were shortlisted after comparing the top-20 hits from both docking scoring functions. To assess binding stability, five of these promising compounds were chosen and run through 100 ns molecular dynamics (MD) simulations in complex with every target protein. Key persistent intermolecular contacts were identified from MD contact frequency histograms, and stability was evaluated using root-mean-square deviation (RMSD) profiles of protein–ligand complexes following equilibration. Additionally, Prime MM-GBSA binding energies (ΔGbind) for the 15 docked complexes were computed, and ligand efficiency was reported. Two substances, BOxNaf1 and BT3, stood out among the screened derivatives as the most stable binders to all three Bcl-2 family targets according to the dual docking and MD analysis approach. When the MM-GBSA and RMSF/rGyr data are considered alongside docking and MD stability, BOxNaf1 and BOxPhCl1 emerge as the most compelling dual/multi-target candidates, whereas BT3, though MD stable, shows weaker MM-GBSA energetics and is retained as a lower-priority backup chemotype.