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Article Dans Une Revue QSAR and Combinatorial Science Année : 2009

Structure-Based Design of Benzoxazoles as new inhibitors for D-Alanyl-D-Alanine Ligase

Résumé

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.

Domaines

Chimie organique

Dates et versions

hal-00443853 , version 1 (04-01-2010)

Identifiants

Citer

I. Tytgat, S. Vandevuer, Isabelle Ortmans, Finton Sirockin, Evelina Colacino, et al.. Structure-Based Design of Benzoxazoles as new inhibitors for D-Alanyl-D-Alanine Ligase. QSAR and Combinatorial Science, 2009, 28 (11-12), pp.1394-1404. ⟨10.1002/qsar.200910054⟩. ⟨hal-00443853⟩
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