NMR structural studies of the supramolecular adducts between a liver cytosolic bile acid binding protein and gadolinium(III)-chelates bearing bile acids residues: molecular determinants of the binding of a hepatospecific magnetic resonance imaging contrast agent

J Med Chem. 2007 Nov 1;50(22):5257-68. doi: 10.1021/jm070397i. Epub 2007 Oct 4.

Abstract

The binding affinities of a selected series of Gd(III) chelates bearing bile acid residues, potential hepatospecific MRI contrast agents, to a liver cytosolic bile acid transporter, have been determined through relaxivity measurements. The Ln(III) complexes of compound 1 were selected for further NMR structural analysis aimed at assessing the molecular determinants of binding. A number of NMR experiments have been carried out on the bile acid-like adduct, using both diamagnetic Y(III) and paramagnetic Gd(III) complexes, bound to a liver bile acid binding protein. The identified protein "hot spots" defined a single binding site located at the protein portal region. The presented findings will serve in a medicinal chemistry approach for the design of hepatocytes-selective gadolinium chelates for liver malignancies detection.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Bile Acids and Salts / chemistry*
  • Bile Acids and Salts / metabolism*
  • Binding Sites
  • Binding, Competitive
  • Carrier Proteins / chemistry
  • Carrier Proteins / metabolism*
  • Cells, Cultured
  • Chelating Agents / chemistry*
  • Contrast Media / chemistry
  • Contrast Media / metabolism*
  • Cytosol / metabolism*
  • Gadolinium*
  • Hepatocytes / metabolism
  • Liver / metabolism*
  • Magnetic Resonance Imaging
  • Magnetic Resonance Spectroscopy
  • Male
  • Membrane Glycoproteins / chemistry
  • Membrane Glycoproteins / metabolism*
  • Models, Molecular
  • Molecular Structure
  • Pentetic Acid / chemistry
  • Protein Binding
  • Rats
  • Rats, Wistar

Substances

  • Bile Acids and Salts
  • Carrier Proteins
  • Chelating Agents
  • Contrast Media
  • Membrane Glycoproteins
  • bile acid binding proteins
  • Pentetic Acid
  • Gadolinium