Design, synthesis and analysis of inhibitors of bacterial aspartate semialdehyde dehydrogenase.
Unsaturated and fluorinated analogues of aspartyl-beta-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 A, or less, from the thiol.
Cox
Russell J
RJ
School of Chemistry, University of Bristol, Cantock's Close, Clifton, Bristol, BS8 1TS, UK. r.j.cox@bris.ac.uk
Gibson
Jennifer S
JS
Hadfield
Andrea T
AT
D001120:Arginine; D001223:Aspartate-Semialdehyde Dehydrogenase / Q000037:antagonists & inhibitors*; D001224:Aspartic Acid / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000494:pharmacology; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors; D001665:Binding Sites; D001667:Binding, Competitive; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013379:Substrate Specificity
D001426:Bacterial Proteins; D004791:Enzyme Inhibitors; C032197:beta-aspartyl phosphate; D001224:Aspartic Acid; D001120:Arginine; D001223:Aspartate-Semialdehyde Dehydrogenase