Article (Scientific journals)
Structure-based design of benzoxazoles as new inhibitors for D-alanyl-D-alanine ligase
Tytgat, Isabelle; Vandevuer, Stéphane; Ortmans, Isabelle et al.
2009In QSAR and Combinatorial Science, 28 (11-12), p. 1394-1404
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Keywords :
Drug Design; antibiotics; D-Ala-D-Ala-Ligase
Abstract :
[en] d-Alanyl – d-alanine ligase is an enzyme which catalyzes the dimerization of d-alanine, and, as such, has an essential role in bacterial cell wall biosynthesis. It has been shown that inhibition of d-alanyl – d-alanine ligase prevents bacterial growth. d-Alanyl – d-alanine ligase represents therefore a viable antimicrobial target. The 3D structure of this enzyme complexed with a phosphinophosphate inhibitor has been reported, which allows for structure-based design studies. Four softwares (LUDI, MCSS, Autodock, and Glide) developed either for fragment or full-molecule docking were compared and scored for their ability to position in the active site four prototypic ligands: two inhibitors, i.e. a phosphinophosphate derivative and d-cycloserine, d-alanine and d-alanyl – d-alanine. Best performances were obtained with Glide and MCSS. A short series of novel derivatives based on a 2-phenylbenzoxazole scaffold was designed de novo on the basis of computational data. The best compound was found to fully inhibit the d-alanyl – d-alanine ligase of E. faecalis with an IC50 of 400 mM.
Disciplines :
Public health, health care sciences & services
Author, co-author :
Tytgat, Isabelle;  Université Catholique de Louvain - UCL > Unité de Pharmacologie cellulaire et moléculaire
Vandevuer, Stéphane;  Université Libre de Bruxelles - ULB > Structure et fonction des membranes biologiques
Ortmans, Isabelle;  Université Libre de Bruxelles - ULB > structure et fonction des membranes biologiques
Sirockin, Finton;  Ecole suprieure de biotechnologie de Strasbourg UMR 7104 > Laboratoire de biologie et génomique structurales IGBMC
Colacino, Evelina;  Université Catholique de Louvain - UCL > Unité de chimie pharmaceutique et radiopharmacie
Van Bambeke, Françoise;  Université Catholique de Louvain - UCL > Unité de pharmacologie cellulaire et moléculaire
Duez, Colette ;  Université de Liège - ULiège > Centre d'ingénierie des protéines
Poupaert, Jacques H;  Université Catholique de Louvain - UCL > Unité de Chimie pharmaceutique et radiopharmacie
Tulkens, Paul M;  Université Catholique de Louvain - UCL > Unité de Pharmacologie cellulaire et moléculaire
Dejaegere, Annick;  Ecole suprieure de biotechnologie de Strasbourg UMR 7104 > Laboratoire de Biologie et Génomique structurales, IGBMC
Prévost, Martine;  Université Libre de Bruxelles - ULB > Structure et fonction des membranes biologiques
Language :
English
Title :
Structure-based design of benzoxazoles as new inhibitors for D-alanyl-D-alanine ligase
Publication date :
16 September 2009
Journal title :
QSAR and Combinatorial Science
ISSN :
1611-020X
eISSN :
1611-0218
Publisher :
Wiley, Weinheim, Germany
Volume :
28
Issue :
11-12
Pages :
1394-1404
Peer reviewed :
Peer Reviewed verified by ORBi
Funders :
F.R.S.-FNRS - Fonds de la Recherche Scientifique [BE]
CNRS - Centre National de la Recherche Scientifique [FR]
INSERM - Institut National de la Santé et de la Recherche Médicale [FR]
Funding number :
F.R.S.-FNRS-PAI P5/33-FRSM3.4.597.06
Available on ORBi :
since 30 December 2011

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