Urokinase Inhibitor Design Based on Pharmacophore Model Derived from Diverse Classes of Inhibitors

A three-dimensional pharmacophore model was developed based on 24 currently available inhibitors, which were rationally selected from 472 compounds with diverse molecular structure and bioactivity, for generating pharmacophore of uPA (Urokinase Plasminogen Activator) inhibitors. The best hypothesis (Hypo1) comprised of five features, namely, one positive ionizable group, one hydrogen-bond acceptor group and three hydrophobic aromatic groups. The correlation coefficient, root mean square deviation and cost difference were 0.973, 0.695, and 94.291 respectively, suggesting that a highly predictive pharmacophore model was successfully obtained. The application of the model showed great success in predicting the activities of 251 known uPA inhibitors (test set) with a correlation coefficient of 0.837, and there was also none of the outcome hypotheses that had similar cost difference and RMS deviation (RMSD) with that of the initial hypothesis generated by Cat-Scramble validation test with 95% confidence level. Accordingly, our model should be reliable in identifying structurally diverse compounds with desired biological activity.