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

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 mu M.