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Modeling the evolution of drug resistance in malaria

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Abstract

Plasmodium falciparum, the causal agent of malaria, continues to evolve resistance to frontline therapeutics such as chloroquine and sulfadoxine-pyrimethamine. Here we study the amino acid replacements in dihydrofolate reductase (DHFR) that confer resistance to pyrimethamine while still binding the natural DHFR substrate, 7,8-dihydrofolate, and cofactor, NADPH. The chain of amino acid replacements that has led to resistance can be inferred in a computer, leading to a broader understanding of the coevolution between the drug and target. This in silico approach suggests that only a small set of specific active site replacements in the proper order could have led to the resistant strains in the wild today. A similar approach can be used on any target of interest to anticipate likely pathways of future resistance for more effective drug development.

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Acknowledgments

Research reported in this publication was supported by the National Institute of General Medical Sciences of the National Institutes of Health under Award Number SC3GM100791. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. The authors would like to thank Patrick Rose and Doug McKenzie as well as the reviewers for valuable suggestions and insightful comments that helped make this a much more complete manuscript.

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Authors and Affiliations

  1. Southwestern College, 900 Otay Lakes Rd., Chula Vista, CA, 91910, USA

    David Hecht

  2. Natural Selection, Inc., 9330 Scranton Rd., San Diego, CA, 92121, USA

    Gary B. Fogel

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  1. David Hecht
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  2. Gary B. Fogel
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Correspondence to David Hecht.

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Hecht, D., Fogel, G.B. Modeling the evolution of drug resistance in malaria. J Comput Aided Mol Des 26, 1343–1353 (2012). https://doi.org/10.1007/s10822-012-9618-2

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  • DOI: https://doi.org/10.1007/s10822-012-9618-2

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