title: Identification and Investigation of Novel Binding Fragments in the Fatty Acid Binding Protein 6 (FABP6).
abstract: 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.
authors: Takeda Cambridge , 418 Cambridge Science Park, Cambridge CB4 0PZ, United Kingdom.
authors: Alan G
authors: AG
authors: Hendrick
authors: Charles River , Chesterford Research Park, Saffron Walden, Essex CB10 1XL, United Kingdom.
authors: Ilka
authors: I
authors: Müller
authors: Takeda Cambridge , 418 Cambridge Science Park, Cambridge CB4 0PZ, United Kingdom.
authors: Henriëtte
authors: H
authors: Willems
authors: Charles River , Chesterford Research Park, Saffron Walden, Essex CB10 1XL, United Kingdom.
authors: Philip M
authors: PM
authors: Leonard
authors: Charles River , Ingram Building, Parkwood Road, Canterbury, Kent CT2 7NH, United Kingdom.
authors: Steve
authors: S
authors: Irving
authors: Takeda Cambridge , 418 Cambridge Science Park, Cambridge CB4 0PZ, United Kingdom.
authors: Richard
authors: R
authors: Davenport
authors: Biomolecular Research Laboratories, Takeda Pharmaceutical Company Limited , 26-1, Muraoka-Higashi 2-chome, Fujisawa 251-8555, Japan.
authors: Takashi
authors: T
authors: Ito
authors: Takeda Cambridge , 418 Cambridge Science Park, Cambridge CB4 0PZ, United Kingdom.
authors: Jenny
authors: J
authors: Reeves
authors: Takeda Cambridge , 418 Cambridge Science Park, Cambridge CB4 0PZ, United Kingdom.
authors: Susanne
authors: S
authors: Wright
authors: Charles River , Chesterford Research Park, Saffron Walden, Essex CB10 1XL, United Kingdom.
authors: Vivienne
authors: V
authors: Allen
authors: Charles River , Chesterford Research Park, Saffron Walden, Essex CB10 1XL, United Kingdom.
authors: Stephen
authors: S
authors: Wilkinson
authors: Takeda Cambridge , 418 Cambridge Science Park, Cambridge CB4 0PZ, United Kingdom.
authors: Helen
authors: H
authors: Heffron
authors: Charles River , Ingram Building, Parkwood Road, Canterbury, Kent CT2 7NH, United Kingdom.
authors: Richard
authors: R
authors: Bazin
authors: Charles River , Chesterford Research Park, Saffron Walden, Essex CB10 1XL, United Kingdom.
authors: Jennifer
authors: J
authors: Turney
authors: Takeda Cambridge , 418 Cambridge Science Park, Cambridge CB4 0PZ, United Kingdom.
authors: Philip J
authors: PJ
authors: Mitchell
mesh_terms: D001647:Bile Acids and Salts / Q000737:chemistry*; D001665:Binding Sites; D018360:Crystallography, X-Ray; D050556:Fatty Acid-Binding Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry*; D005768:Gastrointestinal Hormones / Q000037:antagonists & inhibitors / Q000737:chemistry*; D006801:Humans; D008958:Models, Molecular; D011487:Protein Conformation; D013329:Structure-Activity Relationship; D020349:Surface Plasmon Resonance; D013656:Taurocholic Acid / Q000737:chemistry
chemical_list: D001647:Bile Acids and Salts; D050556:Fatty Acid-Binding Proteins; D005768:Gastrointestinal Hormones; C057275:fatty acid-binding protein 6; D013656:Taurocholic Acid