Structure-based design of benzoxazoles as new inhibitors for D-Alanyl – D-Alanine ligase
(2009) QSAR & Combinatorial Science — Vol. 28, n° 11-12, p. 1394-1404 (2009)
Files
pdfdocument.pdf
Restricted Access - Adobe PDF
- 513.2 KB
Details
- Authors
- Abstract
- 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.
- Affiliations
Citations
Tytgat, I., Vandevuer, S., Ortmans, I., Sirockin, F., Colacino, E., Van Bambeke, F., Duez, C., Poupaert, J., Tulkens, P. M., Dejaegere, A., & Prévost, M. (2009). Structure-based design of benzoxazoles as new inhibitors for D-Alanyl – D-Alanine ligase. QSAR & Combinatorial Science, 28(11-12), 1394-1404. https://doi.org/10.1002/qsar.200910054 (Original work published 2009)