Interpreting steep dose-response curves in early inhibitor discovery

J Med Chem. 2006 Dec 14;49(25):7274-7. doi: 10.1021/jm061103g.


Many screening hits inhibit enzymes with steep dose-response curves, which are considered pathological. Three models might explain these curves: multisite binding, an inhibitor phase transition, or stoichiometric inhibition caused by a high enzyme to Kd ratio. Experiments with promiscuous aggregators, for which steep curves are common, suggest that these curves owe to stoichiometric inhibition, which predicts that IC50 should vary linearly with enzyme concentration. Most steep dose-response curves in screening may be due to this effect.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Acetophenones / chemistry
  • Benzopyrans / chemistry
  • Colloids
  • Congo Red / chemistry
  • Dose-Response Relationship, Drug*
  • Enzyme Inhibitors / administration & dosage
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology*
  • Models, Biological
  • Phenolphthaleins / chemistry
  • Protein Binding
  • beta-Lactamase Inhibitors
  • beta-Lactamases / chemistry


  • Acetophenones
  • Benzopyrans
  • Colloids
  • Enzyme Inhibitors
  • Phenolphthaleins
  • beta-Lactamase Inhibitors
  • Congo Red
  • rottlerin
  • beta-Lactamases