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Modeling the inhibition of quadruple mutant Plasmodium falciparum dihydrofolate reductase by pyrimethamine derivatives

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Abstract

Modeling studies were performed on known inhibitors of the quadruple mutant Plasmodium falciparum dihydrofolate reductase (DHFR). GOLD was used to dock 32 pyrimethamine derivatives into the active site of DHFR obtained from the x-ray crystal structure 1J3K.pdb. Several scoring functions were evaluated and the Molegro Protein-Ligand Interaction Score was determined to have one of the best correlation to experimental pK i . In conjunction with Protein-Ligand Interaction scores, predicted binding modes and key protein-ligand interactions were evaluated and analyzed in order to develop criteria for selecting compounds having a greater chance of activity versus resistant strains of Plasmodium falciparum. This methodology will be used in future studies for selection of compounds for focused screening libraries.

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Acknowledgements

This work is supported by the US Army Medical Research and MaterielCommand under Contract No. W81XWH-06-C-0399. The views, opinions and/or findings contained in this report are those of the authors and should not be construed as an official Department of the Army position, policy or decision unless so designated by other documentation.

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Authors and Affiliations

  1. Natural Selection, Inc., 9330 Scranton Road, Suite 150, San Diego, CA, 92121, USA

    Gary B. Fogel & Mars Cheung

  2. Southwestern College, 900 Otay Lakes Road, Chula Vista, CA, 91910, USA

    Eric Pittman & David Hecht

Authors
  1. Gary B. Fogel
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  2. Mars Cheung
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  3. Eric Pittman
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  4. David Hecht
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Correspondence to David Hecht.

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Fogel, G.B., Cheung, M., Pittman, E. et al. Modeling the inhibition of quadruple mutant Plasmodium falciparum dihydrofolate reductase by pyrimethamine derivatives. J Comput Aided Mol Des 22, 29–38 (2008). https://doi.org/10.1007/s10822-007-9152-9

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  • DOI: https://doi.org/10.1007/s10822-007-9152-9

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