Design, synthesis, and activity of analogues of phosphinothricin as inhibitors of glutamine synthetase.
A new group of potent inhibitors of glutamine synthetase was designed and synthesized. The X-ray structure of bacterial glutamine synthetase complexed with phosphinothricin was used for computer-aided structure-based design of the inhibitors, in which the methyl group of phosphinothricin was chosen as the modification site. Amino and hydroxyl moieties were introduced into the phosphinic acid portion of the lead molecule to interact with ammonium binding site in the active cleft of the enzyme. Designed compounds were synthesized in enantiomerically pure form analogous to l-glutamic acid. In vitro kinetic studies with Escherichia coli glutamine synthetase confirmed the biological activity of the designed inhibitors, which with K(i) values in the micromolar range (K(i) = 0.59 microM for the most potent compound 2) appear to be slightly weaker inhibitors or equipotent to phosphinothricin.
Berlicki
Łukasz
Ł
Department of Bioorganic Chemistry, Faculty of Chemistry, Wrocław University of Technology, Wyb. Wyspiańskiego 27, 50-370 Wrocław, Poland.
Obojska
Agnieszka
A
Forlani
Giuseppe
G
Kafarski
Paweł
P
D000613:Aminobutyrates / Q000138:chemical synthesis* / Q000737:chemistry; D000995:Antitubercular Agents / Q000138:chemical synthesis* / Q000737:chemistry; D003198:Computer Simulation; D015195:Drug Design; D004926:Escherichia coli / Q000201:enzymology; D005974:Glutamate-Ammonia Ligase / Q000037:antagonists & inhibitors* / Q000737:chemistry; D007700:Kinetics; D008958:Models, Molecular; D015394:Molecular Structure; D008970:Molecular Weight; D021281:Quantitative Structure-Activity Relationship; D013237:Stereoisomerism
D000613:Aminobutyrates; D000995:Antitubercular Agents; C003121:phosphinothricin; D005974:Glutamate-Ammonia Ligase