Syzygium malaccense has been traditionally used for its anti-inflammatory and antioxidant properties, yet the specific bioactive compounds responsible for these effects remain insufficiently explored. In this study, HPLC-Q-TOF-MS was employed to systematically identify the metabolites in Syzygium malaccense extracts, leading to the detection of 18 major bioactive compounds, including 9 alkaloids, 5 flavonoids, 2 terpenoids, and 2 phenolic acids. Among them, two compounds were reported for the first time from this plant. The potential anti-inflammatory activity of these compounds was evaluated through molecular docking, molecular dynamics (MD) simulations, and MM/PBSA binding free energy calculations, targeting 5-Lipoxygenase (5-LOX), Cyclooxygenase-2 (COX-2), and Inducible Nitric Oxide Synthase (iNOS). The results revealed that Compounds 10 and 16 exhibited the highest binding affinities, with binding energy values of −122.233 kJ/mol and −137.055 kJ/mol, respectively, indicating strong inhibitory potential. MD simulations over 200 ns demonstrated that ligand binding reduced RMSD and RMSF fluctuations, suggesting enhanced protein stability upon ligand interaction. Additionally, SASA and Rg analyses confirmed that ligand-bound complexes adopted a more compact and less solvent-exposed conformation, reinforcing their structural rigidity and inhibitory effect. The pharmacokinetic evaluation indicated that most identified compounds complied with Lipinski’s rule of five, suggesting favorable bioavailability, although Compounds 10 and 16 exhibited high lipophilicity (Log P > 5), which may require structural modifications to improve absorption properties. This study marks the first comprehensive analysis of S. malaccense metabolites and their inhibitory effects on key inflammatory enzymes, providing a molecular basis for their therapeutic potential.
Fakih et al. (Sun,) studied this question.