Interdisciplinary Bio Central
 
Etc. (Bioinformatics/Computational biology/Molecular modeling)

Urokinase Inhibitor Design Based on Pharmacophore Model Derived from Diverse Classes of Inhibitors
Liu Shui1, Nagakumar Bharatham1, Kavitha Bharatham1 and Keun Woo Lee1,*
1Division of Applied Life Science, Environmental Biotechnology National Core Research Center, Gyeongsang National University, Jinju 660-701, Korea
*Corresponding author
  Published : May 31, 2006
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
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Synopsis

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 shows 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 to 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.

Keyword: Urokinase Inhibitor Design, pharmacophore
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