Fragment screening of inhibitors for MIF tautomerase reveals a cryptic surface binding site.
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.
McLean
Larry R
LR
Discovery Research, Sanofi-aventis, Bridgewater, NJ 08807, USA. Larry.Mclean@sanofi-aventis.com
Zhang
Ying
Y
Li
Hua
H
Choi
Yong-Mi
YM
Han
Zuoning
Z
Vaz
Roy J
RJ
Li
Yi
Y
D001665:Binding Sites; D018360:Crystallography, X-Ray; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D008263:Macrophage Migration-Inhibitory Factors / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D008958:Models, Molecular; D015394:Molecular Structure
D004791:Enzyme Inhibitors; D008263:Macrophage Migration-Inhibitory Factors