Identification and Investigation of Novel Binding Fragments in the Fatty Acid Binding Protein 6 (FABP6)
Fatty acid binding protein 6 (FABP6) is a potential drug discovery target, which, if inhibited, may have a therapeutic benefit for the treatment of diabetes. Currently, there are no published inhibitors of FABP6, and with the target believed to be amenable to fragment-based drug discovery, a structu...
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| Veröffentlicht in: | Journal of medicinal chemistry 2016-09, Vol.59 (17), p.8094-8102 |
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| container_title | Journal of medicinal chemistry |
| container_volume | 59 |
| creator | Hendrick, Alan G Müller, Ilka Willems, Henriëtte Leonard, Philip M Irving, Steve Davenport, Richard Ito, Takashi Reeves, Jenny Wright, Susanne Allen, Vivienne Wilkinson, Stephen Heffron, Helen Bazin, Richard Turney, Jennifer Mitchell, Philip J |
| description | Fatty acid binding protein 6 (FABP6) is a potential drug discovery target, which, if inhibited, may have a therapeutic benefit for the treatment of diabetes. Currently, there are no published inhibitors of FABP6, and with the target believed to be amenable to fragment-based drug discovery, a structurally enabled program was initiated. This program successfully identified fragment hits using the surface plasmon resonance (SPR) platform. Several hits were validated with SAR and were found to be displaced by the natural ligand taurocholate. We report the first crystal structure of human FABP6 in the unbound form, in complex with cholate, and with one of the key fragments. |
| doi_str_mv | 10.1021/acs.jmedchem.6b00869 |
| format | Article |
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We report the first crystal structure of human FABP6 in the unbound form, in complex with cholate, and with one of the key fragments.</description><identifier>ISSN: 0022-2623</identifier><identifier>EISSN: 1520-4804</identifier><identifier>DOI: 10.1021/acs.jmedchem.6b00869</identifier><identifier>PMID: 27500412</identifier><language>eng</language><publisher>United States: American Chemical Society</publisher><subject>Bile Acids and Salts - chemistry ; Binding Sites ; Crystallography, X-Ray ; Fatty Acid-Binding Proteins - antagonists & inhibitors ; Fatty Acid-Binding Proteins - chemistry ; Gastrointestinal Hormones - antagonists & inhibitors ; Gastrointestinal Hormones - chemistry ; Humans ; Models, Molecular ; Protein Conformation ; Structure-Activity Relationship ; Surface Plasmon Resonance ; Taurocholic Acid - chemistry</subject><ispartof>Journal of medicinal chemistry, 2016-09, Vol.59 (17), p.8094-8102</ispartof><rights>Copyright © 2016 American Chemical Society</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-a348t-cd5ac5ff4f3a2d8f52d2032f3ac8da39803a6db45c8f47812b4782c215be77003</citedby><cites>FETCH-LOGICAL-a348t-cd5ac5ff4f3a2d8f52d2032f3ac8da39803a6db45c8f47812b4782c215be77003</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/acs.jmedchem.6b00869$$EPDF$$P50$$Gacs$$H</linktopdf><linktohtml>$$Uhttps://pubs.acs.org/doi/10.1021/acs.jmedchem.6b00869$$EHTML$$P50$$Gacs$$H</linktohtml><link.rule.ids>314,776,780,2752,27053,27901,27902,56713,56763</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/27500412$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Hendrick, Alan G</creatorcontrib><creatorcontrib>Müller, Ilka</creatorcontrib><creatorcontrib>Willems, Henriëtte</creatorcontrib><creatorcontrib>Leonard, Philip M</creatorcontrib><creatorcontrib>Irving, Steve</creatorcontrib><creatorcontrib>Davenport, Richard</creatorcontrib><creatorcontrib>Ito, Takashi</creatorcontrib><creatorcontrib>Reeves, Jenny</creatorcontrib><creatorcontrib>Wright, Susanne</creatorcontrib><creatorcontrib>Allen, Vivienne</creatorcontrib><creatorcontrib>Wilkinson, Stephen</creatorcontrib><creatorcontrib>Heffron, Helen</creatorcontrib><creatorcontrib>Bazin, Richard</creatorcontrib><creatorcontrib>Turney, Jennifer</creatorcontrib><creatorcontrib>Mitchell, Philip J</creatorcontrib><title>Identification and Investigation of Novel Binding Fragments in the Fatty Acid Binding Protein 6 (FABP6)</title><title>Journal of medicinal chemistry</title><addtitle>J. Med. Chem</addtitle><description>Fatty acid binding protein 6 (FABP6) is a potential drug discovery target, which, if inhibited, may have a therapeutic benefit for the treatment of diabetes. Currently, there are no published inhibitors of FABP6, and with the target believed to be amenable to fragment-based drug discovery, a structurally enabled program was initiated. This program successfully identified fragment hits using the surface plasmon resonance (SPR) platform. Several hits were validated with SAR and were found to be displaced by the natural ligand taurocholate. We report the first crystal structure of human FABP6 in the unbound form, in complex with cholate, and with one of the key fragments.</description><subject>Bile Acids and Salts - chemistry</subject><subject>Binding Sites</subject><subject>Crystallography, X-Ray</subject><subject>Fatty Acid-Binding Proteins - antagonists & inhibitors</subject><subject>Fatty Acid-Binding Proteins - chemistry</subject><subject>Gastrointestinal Hormones - antagonists & inhibitors</subject><subject>Gastrointestinal Hormones - chemistry</subject><subject>Humans</subject><subject>Models, Molecular</subject><subject>Protein Conformation</subject><subject>Structure-Activity Relationship</subject><subject>Surface Plasmon Resonance</subject><subject>Taurocholic Acid - chemistry</subject><issn>0022-2623</issn><issn>1520-4804</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2016</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kMtOwzAQRS0EoqXwBwh5CYuU8TgPsywVhUoVsIB15PgRjBKnxGkl_h5DC0s2Y43n3hndQ8g5gykDZNdShel7a7R6M-00rwBEfnNAxixDSFIB6SEZAyAmmCMfkZMQ3gGAM-THZIRFBpAyHJN6qY0fnHVKDq7zVHpNl35rwuDq3U9n6WO3NQ29dV47X9NFL-s2mgJ1ng5vhi7kMHzSmXL6T_Pcd4OJ45xeLma3z_nVKTmysgnmbP9OyOvi7mX-kKye7pfz2SqRPBVDonQmVWZtarlELWyGGoFj7JTQkt8I4DLXVZopYdNCMKxiRYUsq0xRxHwTcrnbu-67j02MUbYuKNM00ptuE0ommOC8yAVGabqTqr4LoTe2XPeulf1nyaD8RlxGxOUv4nKPONou9hc2VZz9mX6ZRgHsBD_2btP7GPj_nV9QPooX</recordid><startdate>20160908</startdate><enddate>20160908</enddate><creator>Hendrick, Alan G</creator><creator>Müller, Ilka</creator><creator>Willems, Henriëtte</creator><creator>Leonard, Philip M</creator><creator>Irving, Steve</creator><creator>Davenport, Richard</creator><creator>Ito, Takashi</creator><creator>Reeves, Jenny</creator><creator>Wright, Susanne</creator><creator>Allen, Vivienne</creator><creator>Wilkinson, Stephen</creator><creator>Heffron, Helen</creator><creator>Bazin, Richard</creator><creator>Turney, Jennifer</creator><creator>Mitchell, Philip J</creator><general>American Chemical Society</general><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></search><sort><creationdate>20160908</creationdate><title>Identification and Investigation of Novel Binding Fragments in the Fatty Acid Binding Protein 6 (FABP6)</title><author>Hendrick, Alan G ; Müller, Ilka ; Willems, Henriëtte ; Leonard, Philip M ; Irving, Steve ; Davenport, Richard ; Ito, Takashi ; Reeves, Jenny ; Wright, Susanne ; Allen, Vivienne ; Wilkinson, Stephen ; Heffron, Helen ; Bazin, Richard ; Turney, Jennifer ; Mitchell, Philip J</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-a348t-cd5ac5ff4f3a2d8f52d2032f3ac8da39803a6db45c8f47812b4782c215be77003</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2016</creationdate><topic>Bile Acids and Salts - chemistry</topic><topic>Binding Sites</topic><topic>Crystallography, X-Ray</topic><topic>Fatty Acid-Binding Proteins - antagonists & inhibitors</topic><topic>Fatty Acid-Binding Proteins - chemistry</topic><topic>Gastrointestinal Hormones - antagonists & inhibitors</topic><topic>Gastrointestinal Hormones - chemistry</topic><topic>Humans</topic><topic>Models, Molecular</topic><topic>Protein Conformation</topic><topic>Structure-Activity Relationship</topic><topic>Surface Plasmon Resonance</topic><topic>Taurocholic Acid - chemistry</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Hendrick, Alan G</creatorcontrib><creatorcontrib>Müller, Ilka</creatorcontrib><creatorcontrib>Willems, Henriëtte</creatorcontrib><creatorcontrib>Leonard, Philip M</creatorcontrib><creatorcontrib>Irving, Steve</creatorcontrib><creatorcontrib>Davenport, Richard</creatorcontrib><creatorcontrib>Ito, Takashi</creatorcontrib><creatorcontrib>Reeves, Jenny</creatorcontrib><creatorcontrib>Wright, Susanne</creatorcontrib><creatorcontrib>Allen, Vivienne</creatorcontrib><creatorcontrib>Wilkinson, Stephen</creatorcontrib><creatorcontrib>Heffron, Helen</creatorcontrib><creatorcontrib>Bazin, Richard</creatorcontrib><creatorcontrib>Turney, Jennifer</creatorcontrib><creatorcontrib>Mitchell, Philip J</creatorcontrib><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><jtitle>Journal of medicinal chemistry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Hendrick, Alan G</au><au>Müller, Ilka</au><au>Willems, Henriëtte</au><au>Leonard, Philip M</au><au>Irving, Steve</au><au>Davenport, Richard</au><au>Ito, Takashi</au><au>Reeves, Jenny</au><au>Wright, Susanne</au><au>Allen, Vivienne</au><au>Wilkinson, Stephen</au><au>Heffron, Helen</au><au>Bazin, Richard</au><au>Turney, Jennifer</au><au>Mitchell, Philip J</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Identification and Investigation of Novel Binding Fragments in the Fatty Acid Binding Protein 6 (FABP6)</atitle><jtitle>Journal of medicinal chemistry</jtitle><addtitle>J. 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We report the first crystal structure of human FABP6 in the unbound form, in complex with cholate, and with one of the key fragments.</abstract><cop>United States</cop><pub>American Chemical Society</pub><pmid>27500412</pmid><doi>10.1021/acs.jmedchem.6b00869</doi><tpages>9</tpages></addata></record> |
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| source | MEDLINE; American Chemical Society (ACS) Journals |
| subjects | Bile Acids and Salts - chemistry Binding Sites Crystallography, X-Ray Fatty Acid-Binding Proteins - antagonists & inhibitors Fatty Acid-Binding Proteins - chemistry Gastrointestinal Hormones - antagonists & inhibitors Gastrointestinal Hormones - chemistry Humans Models, Molecular Protein Conformation Structure-Activity Relationship Surface Plasmon Resonance Taurocholic Acid - chemistry |
| title | Identification and Investigation of Novel Binding Fragments in the Fatty Acid Binding Protein 6 (FABP6) |
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