Molecular docking and 3D-QSAR studies of Yersinia protein tyrosine phosphatase YopH inhibitors

Molecular docking and 3D-QSAR approaches were applied to investigate the interactions of two series of compounds, α-ketocarboxylic acid and squaric acid, with the target protein Yersinia protein tyrosine phosphatase YopH. The studies demonstrate the power of combined docking/QSAR approach to explore the probable binding conformations of YopH inhibitors, and further develop reliable quantitative models for rational drug design. Three-dimensional quantitative structure–activity relationship (QSAR) studies were conducted on two classes of recently explored compounds with known YopH inhibitory activities. Docking studies were employed to position the inhibitors into the YopH active site to determine the probable binding conformation. Good correlations between the predicated binding free energies and the inhibitory activities were found for two subsets of phosphate mimetics: α-ketocarboxylic acid and squaric acid ( R 2 = 0.70 and 0.68, respectively). The docking results also provided a reliable conformational alignment scheme for 3D-QSAR modeling. Comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) were performed based on the docking conformations, giving q 2 of 0.734 and 0.754 for CoMFA and CoMSIA models, respectively. The 3D-QSAR models were significantly improved after removal of an outlier ( q 2 = 0.829 for CoMFA and q 2 = 0.837 for CoMSIA). The predictive ability of the models was validated using a set of compounds that were not included in the training set. Mapping the 3D-QSAR models to the active site of YopH provides new insight into the protein–inhibitor interactions for this enzyme. These results should be applicable to the prediction of the activities of new YopH inhibitors, as well as providing structural implications for designing potent and selective YopH inhibitors as antiplague agents.