Interpreting steep dose-response curves in early inhibitor discovery.
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.
Shoichet
Brian K
BK
Department of Pharmaceutical Chemistry, University of California - San Francisco, 1700 4th Street, San Francisco, California 94158, USA. shoichet@cgl.ucsf.edu
D000098:Acetophenones / Q000737:chemistry; D001578:Benzopyrans / Q000737:chemistry; D003102:Colloids; D003224:Congo Red / Q000737:chemistry; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D008954:Models, Biological; D010635:Phenolphthaleins / Q000737:chemistry; D011485:Protein Binding; D065093:beta-Lactamase Inhibitors; D001618:beta-Lactamases / Q000737:chemistry
D000098:Acetophenones; D001578:Benzopyrans; D003102:Colloids; D004791:Enzyme Inhibitors; D010635:Phenolphthaleins; D065093:beta-Lactamase Inhibitors; D003224:Congo Red; C085746:rottlerin; D001618:beta-Lactamases