Novel α-mangostin derivatives as promising candidates against triple-negative breast cancer: in silico

Benzoylated α-mangostin derivatives demonstrated improved pharmacokinetic and toxicity profiles compared to the parent compound and doxorubicin. In silico screening identified AM-4-Nitrobenzoate, AM-3,5-Dinitrobenzoate, AM-4-Aminobenzoate, and AM-4-Trifluoromethylbenzoate as top candidates with lower binding energies and favorable interactions with key GSK3β residues. Molecular dynamics simulations confirmed stable complex formation, with RMSD values below 3.5 Å and reduced RMSF fluctuations at the catalytic pocket. MM-PBSA analysis highlighted AM-4-Nitrobenzoate as the most potent binder (ΔG_total −18.87 kcal/mol), followed by AM-4-Trifluoromethylbenzoate, AM-4-Aminobenzoate, and AM-3,5-Dinitrobenzoate, while α-mangostin and doxorubicin showed less favorable energies. Structural snapshots reinforced the persistence of ligand orientation and interactions, particularly for para-substituted derivatives. Overall, the integration of docking, MD simulation, and binding free energy analysis underscores para-substituted α-mangostin derivatives, especially AM-4-Nitrobenzoate, as promising scaffolds for GSK3β inhibition in the Wnt/β-catenin pathway relevant to triple-negative breast cancer.