Publication

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

Masini, T., Lacy, B., Monjas, L., Hawksley, D., de Voogd, A. R., Illarionov, B., Iqbal, A., Leeper, F. J., Fischer, M., Kontoyianni, M. & Hirsch, A. K. H., 28-Sep-2015, In : Organic & Biomolecular Chemistry. 13, p. 11263-11277 15 p.

Research output: Contribution to journalArticleAcademicpeer-review

Copy link to clipboard

Documents

  • Validation of a homology model of Mycobacterium tuberculosis DXS

    Final publisher's version, 5.76 MB, PDF document

    Request copy

DOI

  • T Masini
  • B Lacy
  • L Monjas
  • D Hawksley
  • A R de Voogd
  • B Illarionov
  • A Iqbal
  • F J Leeper
  • M Fischer
  • M Kontoyianni
  • A K H Hirsch

The enzyme DXS catalyzes the first, rate-limiting step of the 2-C-methyl-d-erythritol-4-phosphate (MEP, ) 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: ). 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.

Original languageEnglish
Pages (from-to)11263-11277
Number of pages15
JournalOrganic & Biomolecular Chemistry
Volume13
Publication statusPublished - 28-Sep-2015

ID: 24323434