Slow-binding human serine racemase inhibitors from high-throughput screening of combinatorial libraries.
One-bead one-compound combinatorial chemistry together with a high-throughput screen based on fluorescently labeled enzyme allowed the identification of slow binding inhibitors of human serine racemase (hSR). A peptide library of topographically segregated encoded resin beads was synthesized, and several hSR-binding compounds were isolated, identified, and resynthesized for further kinetic study. Of these, several showed inhibitory effects with moderate potency (high micromolar K(I)s) toward hSR. A clear structural motif was identified consisting of 3-phenylpropionic acid and histidine moieties. Importantly, the inhibitors identified showed no structural similarities to the natural substrate, L-serine. Detailed kinetic analyses of the properties of selected inhibitors show that the screening protocol used here selectively identifies slow binding inhibitors. They provide a pharmacophore for the future isolation of more potent ligands that may prove useful in probing and understanding the biological role of hSR.
Dixon
Seth M
SM
Department of Chemistry, University of California, One Shields Avenue, Davis, CA 95616, USA.
Li
Pu
P
Liu
Ruiwu
R
Wolosker
Herman
H
Lam
Kit S
KS
Kurth
Mark J
MJ
Toney
Michael D
MD
D020650:Combinatorial Chemistry Techniques; D004353:Drug Evaluation, Preclinical; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D006801:Humans; D007700:Kinetics; D008024:Ligands; D008958:Models, Molecular; D015394:Molecular Structure; D019151:Peptide Library; D010455:Peptides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D011485:Protein Binding; D019998:Racemases and Epimerases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D013329:Structure-Activity Relationship; D000099300:Serine Racemase
D004791:Enzyme Inhibitors; D008024:Ligands; D019151:Peptide Library; D010455:Peptides; D019998:Racemases and Epimerases; D000099300:Serine Racemase