Prediction of enzyme inhibition and mode of inhibitory action based on calculation of distances between hydrogen bond donor/acceptor groups of the molecule and docking analysis: An application on the discovery of novel effective PTP1B inhibitors.

PTP1B is a protein tyrosine phosphatase involved in insulin receptor desensitization. PTP1B inhibition prolongs the activated state of the receptor, practically enhancing the effect of insulin. Thus PTP1B has become a drug target for the treatment of type II diabetes. PTP1b is an enzyme with multiple binding sites for competitive and allosteric inhibitors. Prediction of inhibitory action using docking analysis has limited success in case of enzymes with multiple binding sites, since the selection of the right crystal structure depends on the kind of inhibitor. In the present study, a two-step strategy for the prediction of PTP1b inhibitory action was applied to 12 compounds. Based on the study of known inhibitors, we isolated the structural characteristics required for binding to each binding site. As a first step, 3D-structures of the molecules were produced and their structural parameters were measured and used for prediction of the binding site of the compound. These results were used for the selection of the appropriate crystal structure for docking analysis of each compound, and the final prediction was based on the estimated binding energies. This strategy effectively predicted the activity of all compounds. A linear correlation was found between estimated binding energy and inhibition measured in vitro (r = -0.894).