500897-92-7Relevant academic research and scientific papers
Design and evaluation of mechanism-based inhibitors of D-alanyl-D-alanine dipeptidase VanX
Yaouancq, Loic,Anissimova, Maria,Badet-Denisot, Marie-Ange,Badet, Bernard
, p. 3573 - 3579 (2007/10/03)
VanX protein is a D-alanyl-D-alanine dipeptidase essential for vancomycin resistance in Enterococcus. It is also a key drug target in circumventing clinical glycopeptide antibiotic resistance. The dipeptide-like compound D-Ala-D- Gly(SC6H4-p-CHF2) (1) was recently reported as the first mechanism-based inhibitor with high affinity for the enzyme but poor inhibitory efficiency (kinact/Kirr = 9320 m-1 s-1) and a high partition ratio (7600). In order to assess the effects of variations in aromatic substituents on the in vitro inhibition properties of 1, we have prepared a few derivatives and analyzed them using the alternative substrate D-Ala-D-Gly(SPh)-OH (15) designed according to a similar strategy. Whereas moving the electrophilic difluoromethyl group to the ortho position slightly improved the inhibition parameters (kinact/ Kirr = 1140 M-1 s-1) with a small decrease in the partition ratio (7200), introduction of a methoxy group in D-Ala-D-ortho/para-(difluoromethyl)phenylthioglycines resulted in a marked decrease in inhibitory efficiency. These results demonstrate the difficulties in improving the leading compound 1 given the restricted space available at the VanX active site. Wiley-VCH Verlag GmbH, 69451 Weinheim, Germany, 2002.
