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Structure-based design of benzoxazoles as new inhibitors for D-Alanyl – D-Alanine ligase

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Tytgat, Isabelle [UCL] Vandevuer, Stéphane Ortmans, Isabelle Sirockin, Finton Colacino, Evelina [UCL] Van Bambeke, Françoise [UCL] Poupaert, Jacques [UCL] Tulkens, Paul M. [UCL] Prévost, Martine

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 μM.

Document type Article de périodique (Journal article) – Article de recherche
Access type Accès restreint
Publication date 2009
Language Français
Journal information "QSAR & Combinatorial Science" - Vol. 28, no. 11-12, p. 1394-1404 (2009)
Peer reviewed yes
Publisher Wiley - V C H Verlag GmbH & Co. KGaA ((Germany) Weinheim)
issn 1611-020X
e-issn 1611-0218
Publication status Publié
Affiliations UCL - MD/FARM - Ecole de pharmacie
UCL - MD/FSIO - Département de physiologie et pharmacologie
Keywords Drug design ; Antibiotics ; Docking ; Binding free energy ; D-Ala-D-Ala ligase
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Bibliographic reference Tytgat, Isabelle ; Vandevuer, Stéphane ; Ortmans, Isabelle ; Sirockin, Finton ; Colacino, Evelina ; et. al. Structure-based design of benzoxazoles as new inhibitors for D-Alanyl – D-Alanine ligase. In: QSAR & Combinatorial Science, Vol. 28, no. 11-12, p. 1394-1404 (2009)
Permanent URL http://hdl.handle.net/2078.1/106618