ORBi: Tytgat Isabelle - Structure-based design of benzoxazoles as new inhibitors for D-alanyl-D-alanine ligase

Reference : Structure-based design of benzoxazoles as new inhibitors for D-alanyl-D-alanine ligase


	Document type :	Scientific journals : Article
	Discipline(s) :	Human health sciences : Public health, health care sciences & services
	To cite this reference:	http://hdl.handle.net/2268/106777

Title :	Structure-based design of benzoxazoles as new inhibitors for D-alanyl-D-alanine ligase
Language :	English
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 - ULg > > 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 > >]
Publication date :	16-Sep-2009
Journal title :	QSAR & Combinatorial Science
Publisher :	Wiley
Volume :	28
Issue/season :	11-12
Pages :	1394-1404
Audience :	International
ISSN :	1611-020X
e-ISSN :	1611-0218
City :	Weinheim
Country :	Germany
Keywords :	[en] 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.
Funders :	Fonds de la Recherche Scientifique (Communauté française de Belgique) - F.R.S.-FNRS-PAI P5/33-FRSM3.4.597.06.CNRS.INSERM
Target :	Researchers ; Professionals
Permalink :	http://hdl.handle.net/2268/106777
DOI :	10.1002/qsar.200910054

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