Metabolic profiling of ligands for the chemokine receptor CXCR3 by liquid chromatography-mass spectrometry coupled to bioaffinity assessment
Chemokine receptors belong to the class of G protein-coupled receptors and are important in the host defense against infections and inflammation. However, aberrant chemokine signaling is linked to different disorders such as cancer, central nervous system and immune disorders, and viral infections [...
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| Veröffentlicht in: | Analytical and bioanalytical chemistry 2015-09, Vol.407 (23), p.7067-7081 |
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| creator | Mladic, Marija Scholten, Danny J Wijtmans, Maikel Falck, David Leurs, Rob Niessen, Wilfried M. A Smit, Martine J Kool, Jeroen |
| description | Chemokine receptors belong to the class of G protein-coupled receptors and are important in the host defense against infections and inflammation. However, aberrant chemokine signaling is linked to different disorders such as cancer, central nervous system and immune disorders, and viral infections [Scholten DJ et al. (2012) Br J Pharmacol 165(6):1617–1643]. Modulating the chemokine receptor function provides new ways of targeting specific diseases. Therefore, discovery and development of drugs targeting chemokine receptors have received considerable attention from the pharmaceutical industry in the past decade. Along with that, the determination of bioactivities of individual metabolites derived from lead compounds towards chemokine receptors is crucial for drug selectivity, pharmacodynamics, and potential toxicity issues. Therefore, advanced analytical methodologies are in high demand. This study is aimed at the optimization of a new analytical method for metabolic profiling with parallel bioaffinity assessment of CXCR3 ligands of the azaquinazolinone and piperazinyl-piperidine class and their metabolites. The method is based on mass spectrometric (MS) identification after liquid chromatographic (LC) separation of metabolic mixtures. The bioaffinity assessment is performed “at-line” via high-resolution nanofractionation onto 96-well plates allowing direct integration of radioligand binding assays. This new method enables identification of metabolites from lead compounds with associated estimation of their individual bioaffinity. Moreover, the identification of the metabolite structures via accurate mass measurements and MS² allows the identification of liable metabolic “hotspots” for further lead optimization. The efficient combination of chemokine receptor ligand binding assays with analytical techniques, involving nanofractionation as linking technology, allows implementation of comprehensive metabolic profiling in an early phase of the drug discovery process. |
| doi_str_mv | 10.1007/s00216-015-8867-z |
| format | Article |
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Along with that, the determination of bioactivities of individual metabolites derived from lead compounds towards chemokine receptors is crucial for drug selectivity, pharmacodynamics, and potential toxicity issues. Therefore, advanced analytical methodologies are in high demand. This study is aimed at the optimization of a new analytical method for metabolic profiling with parallel bioaffinity assessment of CXCR3 ligands of the azaquinazolinone and piperazinyl-piperidine class and their metabolites. The method is based on mass spectrometric (MS) identification after liquid chromatographic (LC) separation of metabolic mixtures. The bioaffinity assessment is performed “at-line” via high-resolution nanofractionation onto 96-well plates allowing direct integration of radioligand binding assays. This new method enables identification of metabolites from lead compounds with associated estimation of their individual bioaffinity. Moreover, the identification of the metabolite structures via accurate mass measurements and MS² allows the identification of liable metabolic “hotspots” for further lead optimization. The efficient combination of chemokine receptor ligand binding assays with analytical techniques, involving nanofractionation as linking technology, allows implementation of comprehensive metabolic profiling in an early phase of the drug discovery process.</description><identifier>ISSN: 1618-2642</identifier><identifier>EISSN: 1618-2650</identifier><identifier>DOI: 10.1007/s00216-015-8867-z</identifier><identifier>PMID: 26164305</identifier><language>eng</language><publisher>Berlin/Heidelberg: Springer Berlin Heidelberg</publisher><subject>Analytical Chemistry ; Analytical methods ; Assessments ; Biochemistry ; Biological activity ; Candidates ; Central nervous system ; Characterization and Evaluation of Materials ; Chemistry ; Chemistry and Materials Science ; Chemokine receptors ; Chemokines ; Chemokines - chemistry ; Chemokines - metabolism ; Chromatography ; Chromatography, High Pressure Liquid - methods ; CXCR3 receptor ; Drugs ; Food Science ; HEK293 Cells ; Histamine ; Humans ; Identification ; immune system ; inflammation ; Laboratory Medicine ; Ligands ; Liquid chromatography ; Mass spectrometry ; Mathematical analysis ; Metabolism ; Metabolites ; metabolomics ; Monitoring/Environmental Analysis ; Nanostructure ; Optimization ; Pharmaceutical industry ; Pharmacodynamics ; pharmacology ; Profiling ; Protein Interaction Mapping - methods ; Proteins ; Receptors, CXCR3 - chemistry ; Receptors, CXCR3 - metabolism ; Reproducibility of Results ; Research Paper ; Scientific imaging ; Sensitivity and Specificity ; Spectrometry, Mass, Electrospray Ionization - methods ; Toxicity</subject><ispartof>Analytical and bioanalytical chemistry, 2015-09, Vol.407 (23), p.7067-7081</ispartof><rights>The Author(s) 2015</rights><rights>COPYRIGHT 2015 Springer</rights><rights>Springer-Verlag Berlin Heidelberg 2015</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c636t-56d0b5e61cc47909934bcb6571df591e7e4a8713c0dcd4e418e9c49841c6bcbd3</citedby><cites>FETCH-LOGICAL-c636t-56d0b5e61cc47909934bcb6571df591e7e4a8713c0dcd4e418e9c49841c6bcbd3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://link.springer.com/content/pdf/10.1007/s00216-015-8867-z$$EPDF$$P50$$Gspringer$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://link.springer.com/10.1007/s00216-015-8867-z$$EHTML$$P50$$Gspringer$$Hfree_for_read</linktohtml><link.rule.ids>230,314,780,784,885,27924,27925,41488,42557,51319</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/26164305$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Mladic, Marija</creatorcontrib><creatorcontrib>Scholten, Danny J</creatorcontrib><creatorcontrib>Wijtmans, Maikel</creatorcontrib><creatorcontrib>Falck, David</creatorcontrib><creatorcontrib>Leurs, Rob</creatorcontrib><creatorcontrib>Niessen, Wilfried M. A</creatorcontrib><creatorcontrib>Smit, Martine J</creatorcontrib><creatorcontrib>Kool, Jeroen</creatorcontrib><title>Metabolic profiling of ligands for the chemokine receptor CXCR3 by liquid chromatography-mass spectrometry coupled to bioaffinity assessment</title><title>Analytical and bioanalytical chemistry</title><addtitle>Anal Bioanal Chem</addtitle><addtitle>Anal Bioanal Chem</addtitle><description>Chemokine receptors belong to the class of G protein-coupled receptors and are important in the host defense against infections and inflammation. However, aberrant chemokine signaling is linked to different disorders such as cancer, central nervous system and immune disorders, and viral infections [Scholten DJ et al. (2012) Br J Pharmacol 165(6):1617–1643]. Modulating the chemokine receptor function provides new ways of targeting specific diseases. Therefore, discovery and development of drugs targeting chemokine receptors have received considerable attention from the pharmaceutical industry in the past decade. Along with that, the determination of bioactivities of individual metabolites derived from lead compounds towards chemokine receptors is crucial for drug selectivity, pharmacodynamics, and potential toxicity issues. Therefore, advanced analytical methodologies are in high demand. This study is aimed at the optimization of a new analytical method for metabolic profiling with parallel bioaffinity assessment of CXCR3 ligands of the azaquinazolinone and piperazinyl-piperidine class and their metabolites. The method is based on mass spectrometric (MS) identification after liquid chromatographic (LC) separation of metabolic mixtures. The bioaffinity assessment is performed “at-line” via high-resolution nanofractionation onto 96-well plates allowing direct integration of radioligand binding assays. This new method enables identification of metabolites from lead compounds with associated estimation of their individual bioaffinity. Moreover, the identification of the metabolite structures via accurate mass measurements and MS² allows the identification of liable metabolic “hotspots” for further lead optimization. The efficient combination of chemokine receptor ligand binding assays with analytical techniques, involving nanofractionation as linking technology, allows implementation of comprehensive metabolic profiling in an early phase of the drug discovery process.</description><subject>Analytical Chemistry</subject><subject>Analytical methods</subject><subject>Assessments</subject><subject>Biochemistry</subject><subject>Biological activity</subject><subject>Candidates</subject><subject>Central nervous system</subject><subject>Characterization and Evaluation of Materials</subject><subject>Chemistry</subject><subject>Chemistry and Materials Science</subject><subject>Chemokine receptors</subject><subject>Chemokines</subject><subject>Chemokines - chemistry</subject><subject>Chemokines - metabolism</subject><subject>Chromatography</subject><subject>Chromatography, High Pressure Liquid - methods</subject><subject>CXCR3 receptor</subject><subject>Drugs</subject><subject>Food Science</subject><subject>HEK293 Cells</subject><subject>Histamine</subject><subject>Humans</subject><subject>Identification</subject><subject>immune system</subject><subject>inflammation</subject><subject>Laboratory Medicine</subject><subject>Ligands</subject><subject>Liquid chromatography</subject><subject>Mass spectrometry</subject><subject>Mathematical analysis</subject><subject>Metabolism</subject><subject>Metabolites</subject><subject>metabolomics</subject><subject>Monitoring/Environmental Analysis</subject><subject>Nanostructure</subject><subject>Optimization</subject><subject>Pharmaceutical industry</subject><subject>Pharmacodynamics</subject><subject>pharmacology</subject><subject>Profiling</subject><subject>Protein Interaction Mapping - methods</subject><subject>Proteins</subject><subject>Receptors, CXCR3 - chemistry</subject><subject>Receptors, CXCR3 - metabolism</subject><subject>Reproducibility of Results</subject><subject>Research Paper</subject><subject>Scientific imaging</subject><subject>Sensitivity and Specificity</subject><subject>Spectrometry, Mass, Electrospray Ionization - methods</subject><subject>Toxicity</subject><issn>1618-2642</issn><issn>1618-2650</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2015</creationdate><recordtype>article</recordtype><sourceid>C6C</sourceid><sourceid>EIF</sourceid><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>AZQEC</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><sourceid>DWQXO</sourceid><sourceid>GNUQQ</sourceid><recordid>eNqNkk2L1TAUhosozof-ADcacDObjknz0XQjDBe_YERQB9yFND3tzdgmnSQV7vwGf7S5dLyMLkSySMh53jc5yVsUzwg-JxjXryLGFRElJryUUtTl7YPimAgiy0pw_PCwZtVRcRLjNc6gJOJxcVQJIhjF_Lj4-RGSbv1oDZqD7-1o3YB8j0Y7aNdF1PuA0haQ2cLkv1sHKICBOeXtzbfNZ4raXWZvFttlJPhJJz8EPW935aRjRHEGk_I2pLBDxi_zCB1KHrXW6763zqYdyhzEOIFLT4pHvR4jPL2bT4urt2--bt6Xl5_efdhcXJZGUJFKLjrcchDEGFY3uGkoa00reE26njcEamBa1oQa3JmOASMSGsMayYgRGezoafF69Z2XdoLO5KODHtUc7KTDTnlt1Z8VZ7dq8D8U45xwgbPB2Z1B8DcLxKQmGw2Mo3bgl6hIzSknsm7Yf6BMSFmLWmT05V_otV-Cyy-xN2SCSlbRTJ2v1KBHUNb1Pl_R5NHBZI13kD8R1AWrRENxJWUWkFVggo8xQH9olGC1z5Fac6RyPNQ-R-o2a57ff6GD4ndwMlCtQMwlN0C4d9d_uL5YRb32Sg_BRnX1pcJE4H00ae7wF2j23_Y</recordid><startdate>20150901</startdate><enddate>20150901</enddate><creator>Mladic, Marija</creator><creator>Scholten, Danny J</creator><creator>Wijtmans, Maikel</creator><creator>Falck, David</creator><creator>Leurs, Rob</creator><creator>Niessen, Wilfried M. 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| subjects | Analytical Chemistry Analytical methods Assessments Biochemistry Biological activity Candidates Central nervous system Characterization and Evaluation of Materials Chemistry Chemistry and Materials Science Chemokine receptors Chemokines Chemokines - chemistry Chemokines - metabolism Chromatography Chromatography, High Pressure Liquid - methods CXCR3 receptor Drugs Food Science HEK293 Cells Histamine Humans Identification immune system inflammation Laboratory Medicine Ligands Liquid chromatography Mass spectrometry Mathematical analysis Metabolism Metabolites metabolomics Monitoring/Environmental Analysis Nanostructure Optimization Pharmaceutical industry Pharmacodynamics pharmacology Profiling Protein Interaction Mapping - methods Proteins Receptors, CXCR3 - chemistry Receptors, CXCR3 - metabolism Reproducibility of Results Research Paper Scientific imaging Sensitivity and Specificity Spectrometry, Mass, Electrospray Ionization - methods Toxicity |
| title | Metabolic profiling of ligands for the chemokine receptor CXCR3 by liquid chromatography-mass spectrometry coupled to bioaffinity assessment |
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