title: Slow-binding human serine racemase inhibitors from high-throughput screening of combinatorial libraries.
abstract: 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.
authors.affiliation: Department of Chemistry, University of California, One Shields Avenue, Davis, CA 95616, USA.
authors.forename: Seth M
authors.initials: SM
authors.lastname: Dixon
authors.forename: Pu
authors.initials: P
authors.lastname: Li
authors.forename: Ruiwu
authors.initials: R
authors.lastname: Liu
authors.forename: Herman
authors.initials: H
authors.lastname: Wolosker
authors.forename: Kit S
authors.initials: KS
authors.lastname: Lam
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Kurth
authors.forename: Michael D
authors.initials: MD
authors.lastname: Toney
mesh_terms: 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
chemical_list: D004791:Enzyme Inhibitors; D008024:Ligands; D019151:Peptide Library; D010455:Peptides; D019998:Racemases and Epimerases; D000099300:Serine Racemase