Journal of Computer-Aided Molecular Design

, Volume 24, Issue 2, pp 157–172 | Cite as

3D-Pharmacophore mapping of thymidine-based inhibitors of TMPK as potential antituberculosis agents

  • Carolina Horta Andrade
  • Kerly F. M. Pasqualoto
  • Elizabeth I. Ferreira
  • Anton J. Hopfinger
Original Paper

Abstract

Tuberculosis (TB) is the primary cause of mortality among infectious diseases. Mycobacterium tuberculosis monophosphate kinase (TMPKmt) is essential to DNA replication. Thus, this enzyme represents a promising target for developing new drugs against TB. In the present study, the receptor-independent, RI, 4D-QSAR method has been used to develop QSAR models and corresponding 3D-pharmacophores for a set of 81 thymidine analogues, and two corresponding subsets, reported as inhibitors of TMPKmt. The resulting optimized models are not only statistically significant with r2 ranging from 0.83 to 0.92 and q2 from 0.78 to 0.88, but also are robustly predictive based on test set predictions. The most and the least potent inhibitors in their respective postulated active conformations, derived from each of the models, were docked in the active site of the TMPKmt crystal structure. There is a solid consistency between the 3D-pharmacophore sites defined by the QSAR models and interactions with binding site residues. Moreover, the QSAR models provide insights regarding a probable mechanism of action of the analogues.

Keywords

4D-QSAR 3D-Pharmacophore Thymidine monophosphate kinase TMPK inhibitors Antituberculosis agents 

Notes

Acknowledgments

The authors are grateful to the CAPES Foundation, a federal scientific agency of Brazil, for scholarship support. This work was also funded by the National Institutes of Health through the NIH Roadmap for Medical Research, Grant 1 R21 GM075775. Information on Novel Preclinical Tools for Predictive ADME-Toxicology can be found at http://grants.nih.gov/grants/guide/rfa-files/RFA-RM-04-023.html. Links to nine initiatives are found here http://nihroadmap. nih.gov/initiatives.asp. Resources of the Laboratory of Molecular Modeling and Design at UNM and The Chem21 Group, Inc. were used in performing this work.

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Copyright information

© Springer Science+Business Media B.V. 2010

Authors and Affiliations

  • Carolina Horta Andrade
    • 1
    • 2
  • Kerly F. M. Pasqualoto
    • 1
  • Elizabeth I. Ferreira
    • 1
  • Anton J. Hopfinger
    • 2
    • 3
  1. 1.Department of Pharmacy, Faculty of Pharmaceutical SciencesUniversity of Sao PauloSao PauloBrazil
  2. 2.College of Pharmacy, MSC09 53601 University of New MexicoAlbuquerqueUSA
  3. 3.The Chem21 Group, Inc.Lake ForestUSA

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