• Open Access

From Zn to Mn: The Study of Novel Manganese-binding Groups in the Search for New Drugs against Tuberculosis

Authors

  • Sarah L. Williams,

    Corresponding author
    1. Department of Chemistry & Biochemistry, University of California San Diego, La Jolla, CA 92093-0365, USA
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  • César Augusto F. de Oliveira,

    1. Department of Chemistry & Biochemistry, University of California San Diego, La Jolla, CA 92093-0365, USA
    2. Howard Hughes Medical Institute, University of California San Diego, La Jolla, CA 92093-0365, USA
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  • H. Vazquez,

    1. Department of Chemistry & Biochemistry, University of California San Diego, La Jolla, CA 92093-0365, USA
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  • J. Andrew McCammon

    1. Department of Chemistry & Biochemistry, University of California San Diego, La Jolla, CA 92093-0365, USA
    2. Howard Hughes Medical Institute, University of California San Diego, La Jolla, CA 92093-0365, USA
    3. Center for Theoretical Biological Physics, University of California San Diego, La Jolla, CA 92093, USA
    4. Department of Pharmacology, University of California San Diego, La Jolla, CA 92093-0365, USA
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Corresponding author: Sarah L. Williams, swilliam@mccammon.ucsd.edu

Abstract

In most eubacteria, apicomplexans, and most plants, including the causal agents for diseases such as malaria, leprosy, and tuberculosis, the methylerythritol phosphate pathway is the route for the biosynthesis of the C5 precursors to the essential isoprenoid class of compounds. Owing to their absence in humans, the enzymes of the methylerythritol phosphate pathway have become attractive targets for drug discovery. This work investigates a new class of inhibitors against the second enzyme of the pathway, 1-deoxy-d-xylulose 5-phosphate reductoisomerase. Inhibition of this enzyme may involve the chelation of a crucial active site Mn ion, and the metal-chelating moieties studied here have previously been shown to be successful in application to the zinc-dependent metalloproteinases. Quantum mechanics and docking calculations presented in this work suggest the transferability of these metal-chelating compounds to Mn-containing 1-deoxy-d-xylulose 5-phosphate reductoisomerase enzyme, as a promising starting point to the development of potent inhibitors.

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