Determination of the bound conformation of a competitive nanomolar inhibitor of mycobacterium tuberculosis type II dehydroquinase by NMR spectroscopy.

The synergy between tuberculosis and the AIDS epidemic, along with the surge of multidrug-resistant isolates of M. tuberculosis, has reaffirmed tuberculosis as a primary public health threat. It is therefore necessary to discover new, safe, and more efficient antibiotics against this disease. On the other hand, mapping the dynamic interactions of inhibitors of a target protein can provide information for the development of more potent inhibitors and consequently, more potent potential drugs. In this context, the conformational binding of our previously reported nanomolar inhibitor of M. tuberculosis type II dehydroquinase, the 3-nitrophenyl derivative 1, was studied using saturation transfer difference (STD) and transferred NOESY experiments. These studies have shown that in the bound state, one conformation of those present in solution of the competitive nanomolar inhibitor 3-nitrophenyl derivative 1 is selected. In the bound conformation, the aromatic ring is slightly shifted from coplanarity, with the double bond and the nitro group of 1 oriented towards the double bond side.
AuthorsVerónica F V Prazeres, Cristina Sánchez-Sixto, Luis Castedo, Angeles Canales, Francisco Javier Cañada, Jesús Jiménez-Barbero, Heather Lamb, Alastair R Hawkins, Concepción González-Bello
JournalChemMedChem (ChemMedChem) Vol. 1 Issue 9 Pg. 990-6 (Sep 2006) ISSN: 1860-7179 [Print] Germany
PMID16952136 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Antitubercular Agents
  • Enzyme Inhibitors
  • Hydro-Lyases
  • 3-dehydroquinate dehydratase
  • Antitubercular Agents (chemistry, pharmacology)
  • Computational Biology
  • Enzyme Inhibitors (chemistry, pharmacology)
  • Hydro-Lyases (antagonists & inhibitors)
  • Magnetic Resonance Spectroscopy
  • Models, Molecular
  • Molecular Conformation
  • Mycobacterium tuberculosis (drug effects, enzymology)
  • Protein Binding

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