Fragment screening of inhibitors for MIF tautomerase reveals a cryptic surface binding site

Bioorg Med Chem Lett. 2010 Mar 15;20(6):1821-4. doi: 10.1016/j.bmcl.2010.02.009. Epub 2010 Feb 6.

Abstract

In the course of a fragment screening campaign by in silico docking followed by X-ray crystallography, a novel binding site for migration inhibitory factor (MIF) inhibitors was demonstrated. The site is formed by rotation of the side-chain of Tyr-36 to reveal a surface binding site in MIF that is hydrophobic and surrounded by aromatic side-chain residues. The crystal structures of two small inhibitors that bind to this site and of a quinolinone inhibitor, that spans the canonical deep pocket near Pro-1 and the new surface binding site, have been solved. These results suggest new opportunities for structure-based design of MIF inhibitors.

MeSH terms

  • Binding Sites
  • Crystallography, X-Ray
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / metabolism
  • Enzyme Inhibitors / pharmacology*
  • Macrophage Migration-Inhibitory Factors / antagonists & inhibitors*
  • Macrophage Migration-Inhibitory Factors / chemistry
  • Macrophage Migration-Inhibitory Factors / metabolism
  • Models, Molecular
  • Molecular Structure

Substances

  • Enzyme Inhibitors
  • Macrophage Migration-Inhibitory Factors