Molecular docking of small ligands to biologically active macromolecules has become a valuable strategy to predict the stability of complexes between potential partners and their binding modes. In this perspective, we applied this computational procedure to rationalize the reported role of polyphenols as inhibitors of the mammalian 20S proteasomes. In particular, polyphenols were shown to modulate each proteasomal activity at different extents both in the constitutive and the inducible enzyme. We performed a flexible molecular docking analysis between a set of polyphenols previously demonstrated to have the highest binding affinity and both the constitutive (from deposited PDB structures) and homology modeled active subunits of the IFN-γ inducible proteasome, to provide insight into the possible mechanism of interaction. Among the tested polyphenols, (-)-epigallocatechin-3-gallate showed the highest affinity for the proteasome subunits, both in terms of intermolecular energy and predicted equilibrium constants, in particular for β5 and β5i subunits (ETotal=-66 kcal/mol, Ki=81.3 μM and E Total=-83.9 kcal/mol, Ki=0.29 μM, respectively), known to be related to the chymotrypsin-like and BrAAP activities. Collectively, polyphenols showed a higher affinity for the inducible subunits, in agreement with previous in vitro studies. Additionally, different contributions to the interaction energy (van der Waals, electrostatic, H-bond) of proteasome-polyphenols complexes were dissected. © 2009 American Chemical Society.
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