Discovery of covalent inhibitors for MIF tautomerase via cocrystal structures with phantom hits from virtual screening

Bioorg Med Chem Lett. 2009 Dec 1;19(23):6717-20. doi: 10.1016/j.bmcl.2009.09.106. Epub 2009 Oct 1.

Abstract

Biochemical and X-ray crystallographic studies confirmed that hydroxyquinoline derivatives identified by virtual screening were actually covalent inhibitors of the MIF tautomerase. Adducts were formed by N-alkylation of the Pro-1 at the catalytic site with a loss of an amino group of the inhibitor.

MeSH terms

  • Crystallography, X-Ray
  • Drug Discovery*
  • Drug Evaluation, Preclinical / methods*
  • Enzyme Inhibitors / chemical synthesis
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology*
  • Hydroxyquinolines / chemical synthesis
  • Hydroxyquinolines / chemistry
  • Hydroxyquinolines / pharmacology*
  • Intramolecular Oxidoreductases / antagonists & inhibitors*
  • Macrophage Migration-Inhibitory Factors / antagonists & inhibitors*
  • Models, Molecular
  • Molecular Structure
  • Structure-Activity Relationship

Substances

  • Enzyme Inhibitors
  • Hydroxyquinolines
  • Macrophage Migration-Inhibitory Factors
  • Intramolecular Oxidoreductases