Computational Exploration of Bcl-2 Inhibitors from Codiaeum variegatum: Docking, MD, and DFT Analyses

Cancer remains a major health issue, and Bcl-2 inhibits apoptosis. This study explored the phytochemicals of Codiaeum variegatum as potential Bcl-2 inhibitors. Receptor–ligand docking was conducted with YASARA, followed by 300 ns MD using AMBER14. ADME and DFT analyses were used to characterize the pharmacokinetics and electronic properties of the inhibitor candidates. The large-scale data generated from the 300-nanosecond MD simulations were further processed to map the energy landscapes using PCA and DCCM analysis in R Studio. We successfully applied the QM-AM1 method to the preparation and execution of molecular docking studies. Among the 17 phytochemical compounds isolated from C. variegatum, taraxerol demonstrated the most promising binding energy, with a docking score of −8.868 kcal/mol, which is comparable to that of the co-crystallized reference ligand, venetoclax. Taraxerol also satisfied the ADME criteria based on Lipinski’s Rule of Five, with only a single rule violation, and DFT calculations confirmed its stability, exhibiting an energy gap of −0.1805 eV. Furthermore, a 300 ns MD simulation revealed that the binding energy of taraxerol, computed using the MM-PBSA method, was more favorable than that of venetoclax, with taraxerol yielding 303.235 kJ/mol in complex with Bcl-2, compared to 291.115 kJ/mol for venetoclax. PCA and DCCM analyses additionally supported the dynamic stability of taraxerol as a potential Bcl-2 inhibitor. Although ADME predictions suggest a favorable safety profile, further in vitro and in vivo validation is required to substantiate its therapeutic potential.