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Design, Synthesis and Analysis of Inhibitors of Bacterial Aspartate Semialdehyde Dehydrogenase

✍ Scribed by Russell J. Cox; Jennifer S. Gibson; Andrea T. Hadfield

Publisher
John Wiley and Sons
Year
2005
Tongue
English
Weight
321 KB
Volume
6
Category
Article
ISSN
1439-4227

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✦ Synopsis

Abstract

Unsaturated and fluorinated analogues of aspartyl‐β‐phosphate were synthesised as potential inhibitors of the bacterial enzyme aspartate semialdehyde dehydrogenase (ASA‐DH). Acetylenic and Z__‐olefinic analogues showed competitive inhibition, but an__ E__‐olefinic analogue was inactive. A monofluoromethylene phosphonate competed poorly, but showed time‐dependent inhibition of ASA‐DH in the absence of phosphate. Simulated docking procedures were used to rationalise the results. These studies showed that substrate and inhibitor binding are mediated by interaction with two active‐site arginine residues, and for likely covalent attachment to the active‐site thiol group, electrophilic carbon atoms should be located 4.5 Å, or less, from the thiol.__

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