Titration-Based Screening for Evaluation of Natural Product Extracts: Identification of an Aspulvinone Family of Luciferase Inhibitors
The chemical diversity of nature has tremendous potential for the discovery of molecular probes and medicinal agents. However, sensitivity of HTS assays to interfering components of crude extracts derived from plants, and macro- and microorganisms has curtailed their use in lead discovery. Here, we...
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| Veröffentlicht in: | Chemistry & biology 2011-11, Vol.18 (11), p.1442-1452 |
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| container_title | Chemistry & biology |
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| creator | Cruz, Patricia G. Auld, Douglas S. Schultz, Pamela J. Lovell, Scott Battaile, Kevin P. MacArthur, Ryan Shen, Min Tamayo-Castillo, Giselle Inglese, James Sherman, David H. |
| description | The chemical diversity of nature has tremendous potential for the discovery of molecular probes and medicinal agents. However, sensitivity of HTS assays to interfering components of crude extracts derived from plants, and macro- and microorganisms has curtailed their use in lead discovery. Here, we describe a process for leveraging the concentration-response curves obtained from quantitative HTS to improve the initial selection of “actives” from a library of partially fractionated natural product extracts derived from marine actinomycetes and fungi. By using pharmacological activity, the first-pass CRC paradigm improves the probability that labor-intensive subsequent steps of reculturing, extraction, and bioassay-guided isolation of active component(s) target the most promising strains and growth conditions. We illustrate how this process identified a family of fungal metabolites as potent inhibitors of firefly luciferase, subsequently resolved in molecular detail by X-ray crystallography.
► Quantitative high-throughput screening of natural product extracts ► Retrospective single-concentration HTS analysis across 35 assays ► Strategy for identification, isolation, and structural elucidation of secondary metabolites ► Cocrystal structure of potent natural product inhibitor with firefly luciferase |
| doi_str_mv | 10.1016/j.chembiol.2011.08.011 |
| format | Article |
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► Quantitative high-throughput screening of natural product extracts ► Retrospective single-concentration HTS analysis across 35 assays ► Strategy for identification, isolation, and structural elucidation of secondary metabolites ► Cocrystal structure of potent natural product inhibitor with firefly luciferase</description><identifier>ISSN: 1074-5521</identifier><identifier>EISSN: 1879-1301</identifier><identifier>DOI: 10.1016/j.chembiol.2011.08.011</identifier><identifier>PMID: 22118678</identifier><language>eng</language><publisher>United States: Elsevier Ltd</publisher><subject>60 APPLIED LIFE SCIENCES ; Aspergillus - chemistry ; BASIC BIOLOGICAL SCIENCES ; Binding Sites ; CRYSTALLOGRAPHY ; Crystallography, X-Ray ; Databases, Protein ; Enzyme Activation - drug effects ; Enzyme Inhibitors - chemistry ; Enzyme Inhibitors - pharmacology ; EVALUATION ; FUNGI ; High-Throughput Screening Assays ; Lactones - chemistry ; Lactones - isolation & purification ; Lactones - pharmacology ; LUCIFERASE ; Luciferases - antagonists & inhibitors ; Luciferases - metabolism ; Magnetic Resonance Spectroscopy ; METABOLITES ; MICROORGANISMS ; Molecular Conformation ; PROBABILITY ; PROBES ; Protein Structure, Tertiary ; SENSITIVITY ; STRAINS ; TARGETS</subject><ispartof>Chemistry & biology, 2011-11, Vol.18 (11), p.1442-1452</ispartof><rights>2011 Elsevier Ltd</rights><rights>Copyright © 2011 Elsevier Ltd. All rights reserved.</rights><rights>2011 Elsevier Ltd. All rights reserved. 2011</rights><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c563t-b7a769e67420a2fd15aba7386237bd61c208ffccdc51ac0b0f8b059d5f09640a3</citedby><cites>FETCH-LOGICAL-c563t-b7a769e67420a2fd15aba7386237bd61c208ffccdc51ac0b0f8b059d5f09640a3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://dx.doi.org/10.1016/j.chembiol.2011.08.011$$EHTML$$P50$$Gelsevier$$Hfree_for_read</linktohtml><link.rule.ids>230,314,777,781,882,3537,27905,27906,45976</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/22118678$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink><backlink>$$Uhttps://www.osti.gov/biblio/1030429$$D View this record in Osti.gov$$Hfree_for_read</backlink></links><search><creatorcontrib>Cruz, Patricia G.</creatorcontrib><creatorcontrib>Auld, Douglas S.</creatorcontrib><creatorcontrib>Schultz, Pamela J.</creatorcontrib><creatorcontrib>Lovell, Scott</creatorcontrib><creatorcontrib>Battaile, Kevin P.</creatorcontrib><creatorcontrib>MacArthur, Ryan</creatorcontrib><creatorcontrib>Shen, Min</creatorcontrib><creatorcontrib>Tamayo-Castillo, Giselle</creatorcontrib><creatorcontrib>Inglese, James</creatorcontrib><creatorcontrib>Sherman, David H.</creatorcontrib><creatorcontrib>Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)</creatorcontrib><title>Titration-Based Screening for Evaluation of Natural Product Extracts: Identification of an Aspulvinone Family of Luciferase Inhibitors</title><title>Chemistry & biology</title><addtitle>Chem Biol</addtitle><description>The chemical diversity of nature has tremendous potential for the discovery of molecular probes and medicinal agents. However, sensitivity of HTS assays to interfering components of crude extracts derived from plants, and macro- and microorganisms has curtailed their use in lead discovery. Here, we describe a process for leveraging the concentration-response curves obtained from quantitative HTS to improve the initial selection of “actives” from a library of partially fractionated natural product extracts derived from marine actinomycetes and fungi. By using pharmacological activity, the first-pass CRC paradigm improves the probability that labor-intensive subsequent steps of reculturing, extraction, and bioassay-guided isolation of active component(s) target the most promising strains and growth conditions. We illustrate how this process identified a family of fungal metabolites as potent inhibitors of firefly luciferase, subsequently resolved in molecular detail by X-ray crystallography.
► Quantitative high-throughput screening of natural product extracts ► Retrospective single-concentration HTS analysis across 35 assays ► Strategy for identification, isolation, and structural elucidation of secondary metabolites ► Cocrystal structure of potent natural product inhibitor with firefly luciferase</description><subject>60 APPLIED LIFE SCIENCES</subject><subject>Aspergillus - chemistry</subject><subject>BASIC BIOLOGICAL SCIENCES</subject><subject>Binding Sites</subject><subject>CRYSTALLOGRAPHY</subject><subject>Crystallography, X-Ray</subject><subject>Databases, Protein</subject><subject>Enzyme Activation - drug effects</subject><subject>Enzyme Inhibitors - chemistry</subject><subject>Enzyme Inhibitors - pharmacology</subject><subject>EVALUATION</subject><subject>FUNGI</subject><subject>High-Throughput Screening Assays</subject><subject>Lactones - chemistry</subject><subject>Lactones - isolation & purification</subject><subject>Lactones - pharmacology</subject><subject>LUCIFERASE</subject><subject>Luciferases - antagonists & inhibitors</subject><subject>Luciferases - metabolism</subject><subject>Magnetic Resonance Spectroscopy</subject><subject>METABOLITES</subject><subject>MICROORGANISMS</subject><subject>Molecular Conformation</subject><subject>PROBABILITY</subject><subject>PROBES</subject><subject>Protein Structure, Tertiary</subject><subject>SENSITIVITY</subject><subject>STRAINS</subject><subject>TARGETS</subject><issn>1074-5521</issn><issn>1879-1301</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2011</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFUU1v1DAUjBCIlsJfqCwunBKenbWTcECUaltWWgES5Ww5_uh6ldiL7azoH-B31-m2KzhxGktvZt48T1GcY6gwYPZ-W8mNHnvrh4oAxhW0VYZnxSlum67ENeDn-Q3NoqSU4JPiVYxbAMBtx14WJ4Rg3LKmPS3-3NgURLLelZ9F1Ar9kEFrZ90tMj6g5V4M08MYeYO-ijQFMaDvwatJJrT8nbUyxQ9opbRL1lh55AqHLuJuGvbWeafRlRjtcDcP1pO0Roe8DK3cxvY2-RBfFy-MGKJ-84hnxc-r5c3ll3L97Xp1ebEuJWV1KvtGNKzTrFkQEMQoTEUvmrplpG56xbAk0BojpZIUCwk9mLYH2ilqoGMLEPVZ8fHgu5v6USuZU-eD-C7YUYQ77oXl_06c3fBbv-c1IbQFmg3eHgx8TJZHaZOWG-md0zJxDDUsSJdJ7x63BP9r0jHx0Uaph0E47afIO2CUAXuwYwemDD7GoM0xCgY-F823_KloPhfNoeUZsvD870OOsqdmM-HTgaDzd-6tDnNY7aRWNsxZlbf_23EPZ-HAqg</recordid><startdate>20111123</startdate><enddate>20111123</enddate><creator>Cruz, Patricia G.</creator><creator>Auld, Douglas S.</creator><creator>Schultz, Pamela J.</creator><creator>Lovell, Scott</creator><creator>Battaile, Kevin P.</creator><creator>MacArthur, Ryan</creator><creator>Shen, Min</creator><creator>Tamayo-Castillo, Giselle</creator><creator>Inglese, James</creator><creator>Sherman, David H.</creator><general>Elsevier Ltd</general><scope>6I.</scope><scope>AAFTH</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>7X8</scope><scope>OTOTI</scope><scope>5PM</scope></search><sort><creationdate>20111123</creationdate><title>Titration-Based Screening for Evaluation of Natural Product Extracts: Identification of an Aspulvinone Family of Luciferase Inhibitors</title><author>Cruz, Patricia G. ; Auld, Douglas S. ; Schultz, Pamela J. ; Lovell, Scott ; Battaile, Kevin P. ; MacArthur, Ryan ; Shen, Min ; Tamayo-Castillo, Giselle ; Inglese, James ; Sherman, David H.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c563t-b7a769e67420a2fd15aba7386237bd61c208ffccdc51ac0b0f8b059d5f09640a3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2011</creationdate><topic>60 APPLIED LIFE SCIENCES</topic><topic>Aspergillus - chemistry</topic><topic>BASIC BIOLOGICAL SCIENCES</topic><topic>Binding Sites</topic><topic>CRYSTALLOGRAPHY</topic><topic>Crystallography, X-Ray</topic><topic>Databases, Protein</topic><topic>Enzyme Activation - drug effects</topic><topic>Enzyme Inhibitors - chemistry</topic><topic>Enzyme Inhibitors - pharmacology</topic><topic>EVALUATION</topic><topic>FUNGI</topic><topic>High-Throughput Screening Assays</topic><topic>Lactones - chemistry</topic><topic>Lactones - isolation & purification</topic><topic>Lactones - pharmacology</topic><topic>LUCIFERASE</topic><topic>Luciferases - antagonists & inhibitors</topic><topic>Luciferases - metabolism</topic><topic>Magnetic Resonance Spectroscopy</topic><topic>METABOLITES</topic><topic>MICROORGANISMS</topic><topic>Molecular Conformation</topic><topic>PROBABILITY</topic><topic>PROBES</topic><topic>Protein Structure, Tertiary</topic><topic>SENSITIVITY</topic><topic>STRAINS</topic><topic>TARGETS</topic><toplevel>online_resources</toplevel><creatorcontrib>Cruz, Patricia G.</creatorcontrib><creatorcontrib>Auld, Douglas S.</creatorcontrib><creatorcontrib>Schultz, Pamela J.</creatorcontrib><creatorcontrib>Lovell, Scott</creatorcontrib><creatorcontrib>Battaile, Kevin P.</creatorcontrib><creatorcontrib>MacArthur, Ryan</creatorcontrib><creatorcontrib>Shen, Min</creatorcontrib><creatorcontrib>Tamayo-Castillo, Giselle</creatorcontrib><creatorcontrib>Inglese, James</creatorcontrib><creatorcontrib>Sherman, David H.</creatorcontrib><creatorcontrib>Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)</creatorcontrib><collection>ScienceDirect Open Access Titles</collection><collection>Elsevier:ScienceDirect:Open Access</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><collection>OSTI.GOV</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Chemistry & biology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Cruz, Patricia G.</au><au>Auld, Douglas S.</au><au>Schultz, Pamela J.</au><au>Lovell, Scott</au><au>Battaile, Kevin P.</au><au>MacArthur, Ryan</au><au>Shen, Min</au><au>Tamayo-Castillo, Giselle</au><au>Inglese, James</au><au>Sherman, David H.</au><aucorp>Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)</aucorp><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Titration-Based Screening for Evaluation of Natural Product Extracts: Identification of an Aspulvinone Family of Luciferase Inhibitors</atitle><jtitle>Chemistry & biology</jtitle><addtitle>Chem Biol</addtitle><date>2011-11-23</date><risdate>2011</risdate><volume>18</volume><issue>11</issue><spage>1442</spage><epage>1452</epage><pages>1442-1452</pages><issn>1074-5521</issn><eissn>1879-1301</eissn><abstract>The chemical diversity of nature has tremendous potential for the discovery of molecular probes and medicinal agents. However, sensitivity of HTS assays to interfering components of crude extracts derived from plants, and macro- and microorganisms has curtailed their use in lead discovery. Here, we describe a process for leveraging the concentration-response curves obtained from quantitative HTS to improve the initial selection of “actives” from a library of partially fractionated natural product extracts derived from marine actinomycetes and fungi. By using pharmacological activity, the first-pass CRC paradigm improves the probability that labor-intensive subsequent steps of reculturing, extraction, and bioassay-guided isolation of active component(s) target the most promising strains and growth conditions. We illustrate how this process identified a family of fungal metabolites as potent inhibitors of firefly luciferase, subsequently resolved in molecular detail by X-ray crystallography.
► Quantitative high-throughput screening of natural product extracts ► Retrospective single-concentration HTS analysis across 35 assays ► Strategy for identification, isolation, and structural elucidation of secondary metabolites ► Cocrystal structure of potent natural product inhibitor with firefly luciferase</abstract><cop>United States</cop><pub>Elsevier Ltd</pub><pmid>22118678</pmid><doi>10.1016/j.chembiol.2011.08.011</doi><tpages>11</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | 60 APPLIED LIFE SCIENCES Aspergillus - chemistry BASIC BIOLOGICAL SCIENCES Binding Sites CRYSTALLOGRAPHY Crystallography, X-Ray Databases, Protein Enzyme Activation - drug effects Enzyme Inhibitors - chemistry Enzyme Inhibitors - pharmacology EVALUATION FUNGI High-Throughput Screening Assays Lactones - chemistry Lactones - isolation & purification Lactones - pharmacology LUCIFERASE Luciferases - antagonists & inhibitors Luciferases - metabolism Magnetic Resonance Spectroscopy METABOLITES MICROORGANISMS Molecular Conformation PROBABILITY PROBES Protein Structure, Tertiary SENSITIVITY STRAINS TARGETS |
| title | Titration-Based Screening for Evaluation of Natural Product Extracts: Identification of an Aspulvinone Family of Luciferase Inhibitors |
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