Tytgat I, Vandevuer S, Ortmans I, Sirockin F, Colacino E, Van Bambeke F, Duez C, Poupaert JH, Tulkens PM, Dejaegere A, Prévost M

Structure-based design of benzoxazoles as new inhibitors for D-alanyl - D-alanine ligas

QSAR Comb. Sci. 28, 2009, No. 11-12, 1394 – 1404


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.