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

Larry R McLean; Ying Zhang; Hua Li; Yong-Mi Choi; Zuoning Han; Roy J Vaz; Yi Li

doi:10.1016/j.bmcl.2010.02.009

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.

Authors

Larry R McLean¹, Ying Zhang, Hua Li, Yong-Mi Choi, Zuoning Han, Roy J Vaz, Yi Li

Affiliation

¹ Discovery Research, Sanofi-aventis, Bridgewater, NJ 08807, USA. [email protected]

PMID: 20185308
DOI: 10.1016/j.bmcl.2010.02.009

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