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 se...
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| Veröffentlicht in: | Journal of medicinal chemistry 2006-04, Vol.49 (8), p.2388-2397 |
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| container_title | Journal of medicinal chemistry |
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| creator | Dixon, Seth M. Li, Pu Liu, Ruiwu Wolosker, Herman Lam, Kit S. Kurth, Mark J. Toney, Michael D. |
| description | 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 Is) 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. |
| doi_str_mv | 10.1021/jm050701c |
| format | Article |
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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 Is) 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.</description><identifier>ISSN: 0022-2623</identifier><identifier>EISSN: 1520-4804</identifier><identifier>DOI: 10.1021/jm050701c</identifier><identifier>PMID: 16610782</identifier><identifier>CODEN: JMCMAR</identifier><language>eng</language><publisher>Washington, DC: American Chemical Society</publisher><subject>Analytical, structural and metabolic biochemistry ; Biological and medical sciences ; Combinatorial Chemistry Techniques ; Drug Evaluation, Preclinical ; Enzyme Activation - drug effects ; Enzyme Inhibitors - chemical synthesis ; Enzyme Inhibitors - chemistry ; Enzyme Inhibitors - pharmacology ; Enzymes and enzyme inhibitors ; Fundamental and applied biological sciences. Psychology ; Humans ; Isomerases ; Kinetics ; Ligands ; Medical sciences ; Miscellaneous ; Models, Molecular ; Molecular Structure ; Peptide Library ; Peptides - chemical synthesis ; Peptides - chemistry ; Peptides - pharmacology ; Pharmacology. Drug treatments ; Protein Binding ; Racemases and Epimerases - antagonists & inhibitors ; Racemases and Epimerases - chemistry ; Structure-Activity Relationship</subject><ispartof>Journal of medicinal chemistry, 2006-04, Vol.49 (8), p.2388-2397</ispartof><rights>Copyright © 2006 American Chemical Society</rights><rights>2006 INIST-CNRS</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-a478t-3bd7a3b32ffc0483ad91bdf504444f01240b7e2d2b3a8daa3c9a28b889babc8a3</citedby><cites>FETCH-LOGICAL-a478t-3bd7a3b32ffc0483ad91bdf504444f01240b7e2d2b3a8daa3c9a28b889babc8a3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://pubs.acs.org/doi/pdf/10.1021/jm050701c$$EPDF$$P50$$Gacs$$H</linktopdf><linktohtml>$$Uhttps://pubs.acs.org/doi/10.1021/jm050701c$$EHTML$$P50$$Gacs$$H</linktohtml><link.rule.ids>315,782,786,2769,27085,27933,27934,56747,56797</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=17707989$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/16610782$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Dixon, Seth M.</creatorcontrib><creatorcontrib>Li, Pu</creatorcontrib><creatorcontrib>Liu, Ruiwu</creatorcontrib><creatorcontrib>Wolosker, Herman</creatorcontrib><creatorcontrib>Lam, Kit S.</creatorcontrib><creatorcontrib>Kurth, Mark J.</creatorcontrib><creatorcontrib>Toney, Michael D.</creatorcontrib><title>Slow-Binding Human Serine Racemase Inhibitors from High-Throughput Screening of Combinatorial Libraries</title><title>Journal of medicinal chemistry</title><addtitle>J. Med. Chem</addtitle><description>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 Is) 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.</description><subject>Analytical, structural and metabolic biochemistry</subject><subject>Biological and medical sciences</subject><subject>Combinatorial Chemistry Techniques</subject><subject>Drug Evaluation, Preclinical</subject><subject>Enzyme Activation - drug effects</subject><subject>Enzyme Inhibitors - chemical synthesis</subject><subject>Enzyme Inhibitors - chemistry</subject><subject>Enzyme Inhibitors - pharmacology</subject><subject>Enzymes and enzyme inhibitors</subject><subject>Fundamental and applied biological sciences. Psychology</subject><subject>Humans</subject><subject>Isomerases</subject><subject>Kinetics</subject><subject>Ligands</subject><subject>Medical sciences</subject><subject>Miscellaneous</subject><subject>Models, Molecular</subject><subject>Molecular Structure</subject><subject>Peptide Library</subject><subject>Peptides - chemical synthesis</subject><subject>Peptides - chemistry</subject><subject>Peptides - pharmacology</subject><subject>Pharmacology. Drug treatments</subject><subject>Protein Binding</subject><subject>Racemases and Epimerases - antagonists & inhibitors</subject><subject>Racemases and Epimerases - chemistry</subject><subject>Structure-Activity Relationship</subject><issn>0022-2623</issn><issn>1520-4804</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2006</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqF0EFv0zAUB3ALgVg3OPAFUC4g7ZDt2U5i5wgF1qFqTLScrWfHaV0Su9iJgG9PplbrBWm-vIN__uv5T8gbClcUGL3e9VCCAGqekRktGeSFhOI5mQEwlrOK8TNyntIOADhl_CU5o1VFQUg2I5tVF37nH51vnN9ki7FHn61sdN5m39HYHpPNbv3WaTeEmLI2hj5buM02X29jGDfb_ThkKxOt9Q_vQ5vNQ6-dx0k77LKl0xGjs-kVedFil-zr47wgP758Xs8X-fLbze38wzLHQsgh57oRyDVnbWugkBybmuqmLaGYTguUFaCFZQ3THGWDyE2NTGopa43aSOQX5P0hdx_Dr9GmQfUuGdt16G0Yk6qELHnB4ElIa15DAWyClwdoYkgp2lbto-sx_lUU1EP96rH-yb49ho66t81JHvuewLsjwGSwayN649LJCQGilvXk8oNzabB_Hu8x_px-wEWp1vcr9an6ereuyzt1f8pFk9QujNFPJf9nwX-df6i6</recordid><startdate>20060420</startdate><enddate>20060420</enddate><creator>Dixon, Seth M.</creator><creator>Li, Pu</creator><creator>Liu, Ruiwu</creator><creator>Wolosker, Herman</creator><creator>Lam, Kit S.</creator><creator>Kurth, Mark J.</creator><creator>Toney, Michael D.</creator><general>American Chemical Society</general><scope>BSCLL</scope><scope>IQODW</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7QO</scope><scope>8FD</scope><scope>FR3</scope><scope>P64</scope><scope>7X8</scope></search><sort><creationdate>20060420</creationdate><title>Slow-Binding Human Serine Racemase Inhibitors from High-Throughput Screening of Combinatorial Libraries</title><author>Dixon, Seth M. ; Li, Pu ; Liu, Ruiwu ; Wolosker, Herman ; Lam, Kit S. ; Kurth, Mark J. ; Toney, Michael D.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-a478t-3bd7a3b32ffc0483ad91bdf504444f01240b7e2d2b3a8daa3c9a28b889babc8a3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2006</creationdate><topic>Analytical, structural and metabolic biochemistry</topic><topic>Biological and medical sciences</topic><topic>Combinatorial Chemistry Techniques</topic><topic>Drug Evaluation, Preclinical</topic><topic>Enzyme Activation - drug effects</topic><topic>Enzyme Inhibitors - chemical synthesis</topic><topic>Enzyme Inhibitors - chemistry</topic><topic>Enzyme Inhibitors - pharmacology</topic><topic>Enzymes and enzyme inhibitors</topic><topic>Fundamental and applied biological sciences. Psychology</topic><topic>Humans</topic><topic>Isomerases</topic><topic>Kinetics</topic><topic>Ligands</topic><topic>Medical sciences</topic><topic>Miscellaneous</topic><topic>Models, Molecular</topic><topic>Molecular Structure</topic><topic>Peptide Library</topic><topic>Peptides - chemical synthesis</topic><topic>Peptides - chemistry</topic><topic>Peptides - pharmacology</topic><topic>Pharmacology. Drug treatments</topic><topic>Protein Binding</topic><topic>Racemases and Epimerases - antagonists & inhibitors</topic><topic>Racemases and Epimerases - chemistry</topic><topic>Structure-Activity Relationship</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Dixon, Seth M.</creatorcontrib><creatorcontrib>Li, Pu</creatorcontrib><creatorcontrib>Liu, Ruiwu</creatorcontrib><creatorcontrib>Wolosker, Herman</creatorcontrib><creatorcontrib>Lam, Kit S.</creatorcontrib><creatorcontrib>Kurth, Mark J.</creatorcontrib><creatorcontrib>Toney, Michael D.</creatorcontrib><collection>Istex</collection><collection>Pascal-Francis</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Biotechnology Research Abstracts</collection><collection>Technology Research Database</collection><collection>Engineering Research Database</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>MEDLINE - Academic</collection><jtitle>Journal of medicinal chemistry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Dixon, Seth M.</au><au>Li, Pu</au><au>Liu, Ruiwu</au><au>Wolosker, Herman</au><au>Lam, Kit S.</au><au>Kurth, Mark J.</au><au>Toney, Michael D.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Slow-Binding Human Serine Racemase Inhibitors from High-Throughput Screening of Combinatorial Libraries</atitle><jtitle>Journal of medicinal chemistry</jtitle><addtitle>J. Med. Chem</addtitle><date>2006-04-20</date><risdate>2006</risdate><volume>49</volume><issue>8</issue><spage>2388</spage><epage>2397</epage><pages>2388-2397</pages><issn>0022-2623</issn><eissn>1520-4804</eissn><coden>JMCMAR</coden><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 Is) 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. 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| ispartof | Journal of medicinal chemistry, 2006-04, Vol.49 (8), p.2388-2397 |
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| subjects | Analytical, structural and metabolic biochemistry Biological and medical sciences Combinatorial Chemistry Techniques Drug Evaluation, Preclinical Enzyme Activation - drug effects Enzyme Inhibitors - chemical synthesis Enzyme Inhibitors - chemistry Enzyme Inhibitors - pharmacology Enzymes and enzyme inhibitors Fundamental and applied biological sciences. Psychology Humans Isomerases Kinetics Ligands Medical sciences Miscellaneous Models, Molecular Molecular Structure Peptide Library Peptides - chemical synthesis Peptides - chemistry Peptides - pharmacology Pharmacology. Drug treatments Protein Binding Racemases and Epimerases - antagonists & inhibitors Racemases and Epimerases - chemistry Structure-Activity Relationship |
| title | Slow-Binding Human Serine Racemase Inhibitors from High-Throughput Screening of Combinatorial Libraries |
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