Combining molecular docking and molecular dynamics simulation to explore Quercetin's affinity and interactions with wild-type and mutated phosphatase and tensin homolog (PTEN)

This study investigates the interaction of Quercetin with wild-type and mutant PTEN, a key tumor suppressor inactivated in many cancers. Using molecular docking and MD simulations, we found Quercetin has a significantly higher binding affinity for mutant PTEN, with docking energies of -6.44 kcal/mol versus -6.08 kcal/mol for the wild-type. This was corroborated by MMPBSA calculations, showing a substantially more favorable binding energy for the mutant complex (-116.040 ± 16.691 kJ/mol) versus the wild-type (-68.088 ± 14.761 kJ/mol). This suggests Quercetin's potential to stabilize the mutant protein and restore lost function. Energetic decomposition revealed van der Waals interactions dominate the binding. Furthermore, root mean square deviation (RMSD) and root mean square fluctuation (RMSF) analyses indicated that Quercetin stabilizes the mutated PTEN while mildly destabilizing the wild-type. Solvent-accessible surface area (SASA) studies further showed Quercetin modulates PTEN's conformational flexibility. These findings highlight the therapeutic potential of Quercetin in addressing PTEN-related tumorigenesis. Given its favorable bioactivity and safety profile, Quercetin is a strong candidate for drug repurposing in cancers with PTEN dysfunction, laying the groundwork for its development as a targeted therapeutic agent.