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Journal of Computer-Aided Molecular Design

, Volume 23, Issue 8, pp 555–569 | Cite as

Development and NMR validation of minimal pharmacophore hypotheses for the generation of fragment libraries enriched in heparanase inhibitors

  • Rafael Gozalbes
  • Silvia Mosulén
  • Rodrigo J. Carbajo
  • Antonio Pineda-Lucena
Article

Abstract

A combined strategy based on the development of pharmacophore hypotheses and NMR approaches is reported for the identification of novel inhibitors of heparanase, a key enzyme involved in tumor metastasis through the remodeling of the subepithelial and subendothelial basement membranes, resulting in the dissemination of metastatic cancer cells. Several pharmacophore hypotheses were initially developed from the most active heparanase inhibitors known to date and, after their application to a pool of 27 known heparanase inhibitors and a database of 1,120 compounds approved by the FDA, a four-point pharmacophore model was selected as the most predictive. This model was subsequently applied to a database of 686 chemical fragments, and a subset of 100 fragments accomplishing completely or partially the four-point model was selected to perform nuclear magnetic resonance experiments to validate the hypothesis. The experimental studies confirmed the reliability of our pharmacophore model, its applicability to in silico databases in order to reduce the number of compounds to be experimentally screened, and the possibility of generating fragment libraries enriched in heparanase inhibitors.

Keywords

Pharmacophore Fragment-based screening NMR Heparanase Inhibitor 

Notes

Acknowledgments

The authors wish to thank the Spanish Ministerio de Ciencia e Innovación (MCINN, SAF2008-01845), the Fundación de Investigación Médica Mutua Madrileña and the Centro de Investigación Príncipe Felipe for economic support. We also acknowledge the financial support provided by the Access to Research Infrastructures activity in the 6th FP of the EC (Contract #RII3-026145, EU-NMR), and the CERM for providing technical support. S.M. and R.J.C are recipients of a FPI predoctoral fellowship and a contract of the Ramón y Cajal program from the MCINN, respectively.

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Copyright information

© Springer Science+Business Media B.V. 2009

Authors and Affiliations

  • Rafael Gozalbes
    • 1
  • Silvia Mosulén
    • 1
  • Rodrigo J. Carbajo
    • 1
  • Antonio Pineda-Lucena
    • 1
  1. 1.Structural Biology Laboratory, Department of Medicinal ChemistryCentro de Investigación Príncipe FelipeValenciaSpain

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