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 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.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 2388-2397 |
| Number of pages | 10 |
| Journal | Journal of Medicinal Chemistry |
| Volume | 49 |
| Issue number | 8 |
| DOIs | |
| State | Published - Apr 20 2006 |
Fingerprint
ASJC Scopus subject areas
- Organic Chemistry
Cite this
Slow-binding human serine racemase inhibitors from high-throughput screening of combinatorial libraries. / Dixon, Seth M.; Li, Pu; Liu, Ruiwu; Wolosker, Herman; Lam, Kit; Kurth, Mark J.; Toney, Michael D.
In: Journal of Medicinal Chemistry, Vol. 49, No. 8, 20.04.2006, p. 2388-2397.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Slow-binding human serine racemase inhibitors from high-throughput screening of combinatorial libraries
AU - Dixon, Seth M.
AU - Li, Pu
AU - Liu, Ruiwu
AU - Wolosker, Herman
AU - Lam, Kit
AU - Kurth, Mark J.
AU - Toney, Michael D.
PY - 2006/4/20
Y1 - 2006/4/20
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=33646111450&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=33646111450&partnerID=8YFLogxK
U2 - 10.1021/jm050701c
DO - 10.1021/jm050701c
M3 - Article
C2 - 16610782
AN - SCOPUS:33646111450
VL - 49
SP - 2388
EP - 2397
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
SN - 0022-2623
IS - 8
ER -