English   español  
Please use this identifier to cite or link to this item: http://hdl.handle.net/10261/57787
Share/Impact:
Statistics
logo share SHARE logo core CORE   Add this article to your Mendeley library MendeleyBASE

Visualizar otros formatos: MARC | Dublin Core | RDF | ORE | MODS | METS | DIDL
Exportar a otros formatos:

Title

Competitive Inhibitors of Helicobacter pylori Type II Dehydroquinase: Synthesis, Biological Evaluation, and NMR Studies

AuthorsSánchez-Sixto, C.; Prazeres, V.F.; Castedo, L.; Suh, S.W.; Lamb, H.; Hawkins, A.R.; Cañada, F. Javier ; Jiménez-Barbero, Jesús ; González-Bello, C.
KeywordsCompetitive inhibitors
dehydroquinase
helicobacter pylori
saturation transfer difference
Issue Date19-May-2008
PublisherWiley-VCH
CitationChemMedChem, 3 (5) : 756-770
AbstractSeveral 3-heteroaryl analogs of the known dehydroquinase inhibitor (1R,4R,5R)-1,4,5-trihydroxy-2-cyclohexene-1-carboxylic acid (4) were synthesized and tested as inhibitors of Helicobacter pylori type II dehydroquinase, the third enzyme of the shikimic acid pathway. All of these compounds proved to be reversible competitive inhibitiors of this enzyme and proved to be, with the exception of nitrile 8 e, more potent than the parent inhibitor 4 (Ki=370  μM). The 2-thienyl derivative 8 b was found to be the most potent inhibitor of the series and has a Ki value of 540 nM, which is almost seven hundred times lower than that of the parent inhibitor. The 3-nitrothienyl derivative 8 d and 2-furanyl derivative 8 a also had a good affinity of 1 μM. The conformation of the potent competitive inhibitor 8 b, when bound in the active site of the H. pylori enzyme, was elucidated by 1D-selective inversion NOE, Saturation Transfer Difference (STD) and transferred NOESY NMR experiments. One of the conformations that exists in solution for the potent competitive inhibitor 2-thienyl derivative 8 b is selected when it is bound to the active site of the enzyme. In the bound conformation derivative 8 b has the sulfur atom of its thienyl group oriented towards the double bond of the cyclohexene moiety. The large STD effects observed for the aromatic protons of 8 b show that it is the thiophene side of the ligand that makes closest contact with enzyme protons. Docking studies using GOLD3.0.1 suggest that the conformation determined by NMR allows strong lipophilic interactions with the enzyme residues Pro9, Asn10, Ile11, Gly78 and Ala 79. Competitive STD experiments carried out with high-, medium- and low-affinity ligands 8 b, 5 d and 5 f show that they all bind in the same site of Helicobacter pylori dehydroquinase
Description15 páginas, 10 figuras, 1 tabla, 5 esquemas -- PAGS nros. 756-770
Publisher version (URL)http://dx.doi.org/10.1002/cmdc.200700307
URIhttp://hdl.handle.net/10261/57787
DOI10.1002/cmdc.200700307
ISSN1860-7179
E-ISSN1860-7187
Appears in Collections:(CIB) Artículos
Files in This Item:
File Description SizeFormat 
restringido.pdf21,67 kBAdobe PDFThumbnail
View/Open
Show full item record
Review this work
 

Related articles:


WARNING: Items in Digital.CSIC are protected by copyright, with all rights reserved, unless otherwise indicated.