AZ12 Based Design of PDK2 Inhibitors

Abstract

The binding modes and binding affinities of a synthetic PDK2 inhibitor, AZ12 (N-{4-[(ethylanilino)sulfonyl]-2-methylphenyl}-3,3,3-trifluoro-2-hydroxy-2-methylpropanamide) and its analogues with the PDK2 receptor are reported in this work. To study the molecular basis of the interaction and affinity of binding of AZ12 and similar compounds, the docking site of AZ12 at the lipoamide binding site has been analyzed in detail. We have applied a flexible docking approach to predict the ‘preferable’ binding structure of the ligands in the lipoyl domain. It is found that most of the ligand is embedded into the hydrophobic part of the protein binding site. A total of 418 structures similar to AZ12 were docked into the receptor grid. All of these, except one, found suitable poses and their docking scores range from -13.19 to -3.37. Our results show that compounds similar to AZ12 bind in PDK2 at the same site and also in a position and orientation very similar to AZ12. We then compared the properties of the top-ranked ligand with those of AZ12. Both were found to have similar shape and HOMO and LUMO energies