Abstract
Background: Oral cancer is a major problem in dentistry and remains a major global health issue. In oral cancer, BCL-2, which plays a role in regulating cell death, is overexpressed, thus leading to its progression and resistance to chemotherapy. Clausena excavata contains a coumarin called nordentatin, which has been shown to have anticancer properties. Particularly with regard to its function as a BCL-2 inhibitor, the underlying molecular mechanism is yet unknown. Objectives: The aim of this study was to determine the potential of nordentatin as a BCL-2 protein inhibitor through molecular docking and then validate it with molecular dynamics. Materials and Methods: Nordentatin's ADMET and bioactivity were estimated in silico. AutoDock Vina was used for molecular docking against BCL-2 using methotrexate as a comparison ligand and venetoclax as a reference ligand. PyMOL and Biovia Discovery Studio were then used for interaction analysis. Complex stability was assessed using a YASARA molecular dynamics simulation. Results: Nordentatin exhibits potential as an anti-inflammatory, anti-angiogenic, antioxidant, and anticancer drug based on bioactivity predictions. ADMET analysis showed that this compound is readily absorbed in the intestine, has moderate clearance, limited penetration into the central nervous system, and low toxicity, thus indicating a favorable pharmacokinetic and safety profile. Molecular docking results show that nordentatin has a fairly strong binding affinity for BCL-2 with a value of −7.4 kcal/mol, which is mainly influenced by hydrophobic and electrostatic interactions. Molecular dynamics simulations indicate that the BCL-2–nordentatin complex remains stable, with an RMSD value below ±2 Å, a compact Rg profile, and favorable RMSF fluctuations. Conclusion: The results indicate that nordentatin binds strongly and stably to BCL-2, thus offering potential for development as a BCL-2 inhibitor for oral cancer therapy.