[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 CNRS - Centre National de la Recherche Scientifique INSERM - Institut National de la Santé et de la Recherche Médicale
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