title: Structural analysis of ibuprofen binding to human adipocyte fatty-acid binding protein (FABP4).
abstract: Inhibition of human adipocyte fatty-acid binding protein (FABP4) has been proposed as a treatment for type 2 diabetes, fatty liver disease and atherosclerosis. However, FABP4 displays a naturally low selectivity towards hydrophobic ligands, leading to the possibility of side effects arising from cross-inhibition of other FABP isoforms. In a search for structural determinants of ligand-binding selectivity, the binding of FABP4 towards a group of small molecules structurally related to the nonsteroidal anti-inflammatory drug ibuprofen was analyzed through X-ray crystallography. Several specific hydrophobic interactions are shown to enhance the binding affinities of these compounds, whereas an aromatic edge-to-face interaction is proposed to determine the conformation of bound ligands, highlighting the importance of aromatic interactions in hydrophobic environments.
authors: Protein Crystallography Station, Bioscience Division, Los Alamos National Laboratory, Los Alamos, NM 87545, USA.
authors: Javier M
authors: JM
authors: González
authors: Protein Crystallography Station, Bioscience Division, Los Alamos National Laboratory, Los Alamos, NM 87545, USA.
authors: S Zoë
authors: SZ
authors: Fisher
mesh_terms: D003460:Crystallization; D018360:Crystallography, X-Ray; D050556:Fatty Acid-Binding Proteins / Q000737:chemistry* / Q000378:metabolism*; D006801:Humans; D007052:Ibuprofen / Q000737:chemistry* / Q000378:metabolism*; D008024:Ligands; D008958:Models, Molecular
chemical_list: C493410:FABP4 protein, human; D050556:Fatty Acid-Binding Proteins; D008024:Ligands; D007052:Ibuprofen
keywords: ALBP; FABP4; aP2; adipocyte; human fatty-acid binding protein; iLBP; ibuprofen