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Issue 46, 2015
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Validation of a homology model of Mycobacterium tuberculosis DXS: rationalization of observed activities of thiamine derivatives as potent inhibitors of two orthologues of DXS

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Abstract

The enzyme DXS catalyzes the first, rate-limiting step of the 2-C-methyl-D-erythritol-4-phosphate (MEP, 1) pathway using thiamine diphosphate (ThDP) as cofactor; the DXS-catalyzed reaction constitutes also the first step in vitamin B1 and B6 metabolism in bacteria. DXS is the least studied among the enzymes of this pathway in terms of crystallographic information, with only one complete crystal structure deposited in the Protein Data Bank (Deinococcus radiodurans DXS, PDB: 2O1X). We synthesized a series of thiamine and ThDP derivatives and tested them for their biochemical activity against two DXS orthologues, namely D. radiodurans DXS and Mycobacterium tuberculosis DXS. These experimental results, combined with advanced docking studies, led to the development and validation of a homology model of M. tuberculosis DXS, which, in turn, will guide medicinal chemists in rationally designing potential inhibitors for M. tuberculosis DXS.

Graphical abstract: Validation of a homology model of Mycobacterium tuberculosis DXS: rationalization of observed activities of thiamine derivatives as potent inhibitors of two orthologues of DXS

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Publication details

The article was received on 07 Aug 2015, accepted on 14 Sep 2015 and first published on 15 Sep 2015


Article type: Paper
DOI: 10.1039/C5OB01666E
Author version available: Download Author version (PDF)
Citation: Org. Biomol. Chem., 2015,13, 11263-11277
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    Validation of a homology model of Mycobacterium tuberculosis DXS: rationalization of observed activities of thiamine derivatives as potent inhibitors of two orthologues of DXS

    T. Masini, B. Lacy, L. Monjas, D. Hawksley, A. R. de Voogd, B. Illarionov, A. Iqbal, F. J. Leeper, M. Fischer, M. Kontoyianni and A. K. H. Hirsch, Org. Biomol. Chem., 2015, 13, 11263
    DOI: 10.1039/C5OB01666E

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