Molecular Dynamics Simulation and MM/PBSA Analysis of α-Mangostin Stabilization in Soluplus^® and Kollidon^® VA64-Based...

α-Mangostin (αM) is a natural xanthone with broad pharmacological activity; however, its therapeutic use is limited by poor aqueous solubility and low bioavailability. Amorphous Solid Dispersion (ASD) is a practical strategy for improving poorly soluble drugs; however, polymer selection remains a critical step that should be supported by molecular-level evidence of drug-polymer compatibility. In this study, 500 ns Molecular Dynamics (MD) simulations followed by Molecular Mechanics/Poisson-Boltzmann Surface Area (MM/PBSA) analysis were used to compare the association of αM with Soluplus^® and Kollidon^® VA64 at drug-to-polymer ratios of 1:1, 1:3, 1:5, and 1:7. All systems reached relatively stable configurations, but the two polymers stabilized αM differently. Soluplus^® 1:3 produced the most stable global structure based on RMSD, whereas Kollidon^® VA64 showed its best stability at 1:7. Soluplus^® displayed a stronger interaction network: at 1:7, it generated 1150 hydrogen-bond pairs with 231.17% cumulative occupancy, compared with 900 pairs and 96.69% for Kollidon^® VA64. Binding energies ranged from -126.24 to -484.09 kJ/mol for Soluplus^® and from -71.58 to -382.42 kJ/mol for Kollidon^® VA64, mainly driven by van der Waals contacts. These results indicate that Soluplus^® provides a more favorable molecular environment for further αM ASD development.