| Autor: |
M. Dixon, Seth, Li, Pu, Liu, Ruiwu, Wolosker, Herman, S. Lam, Kit, J. Kurth, Mark, D. Toney, Michael |
| Zdroj: |
Journal of Medicinal Chemistry; April 2006, Vol. 49 Issue: 8 p2388-2397, 10p |
| Abstrakt: |
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 KIs) 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. |
| Databáze: |
Supplemental Index |
| Externí odkaz: |
|
