title: On the different experimental manifestations of two-state 'induced-fit' binding of drugs to their cellular targets.
abstract: 'Induced-fit' binding of drugs to a target may lead to high affinity, selectivity and a long residence time, and this mechanism has been proposed to apply to many drugs with high clinical efficacy. It is a multistep process that initially involves the binding of a drug to its target to form a loose RL complex and a subsequent isomerization/conformational change to yield a tighter binding R'L state. Equations with the same mathematical form may also describe the binding of bivalent antibodies and related synthetic drugs. Based on a selected range of 'microscopic' rate constants and variables such as the ligand concentration and incubation time, we have simulated the experimental manifestations that may go along with induced-fit binding. Overall, they validate different experimental procedures that have been used over the years to identify such binding mechanisms. However, they also reveal that each of these manifestations only becomes perceptible at particular combinations of rate constants. The simulations also show that the durable nature of R'L and the propensity of R'L to be formed repeatedly before the ligand dissociates will increase the residence time. This review may help pharmacologists and medicinal chemists obtain preliminary indications for identifying an induced-fit mechanism.
authors.affiliation: Department of Molecular and Biochemical Pharmacology, Vrije Universiteit Brussel, Brussels, Belgium.
authors.forename: Georges
authors.initials: G
authors.lastname: Vauquelin
authors.affiliation: Department of Molecular and Biochemical Pharmacology, Vrije Universiteit Brussel, Brussels, Belgium.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Van Liefde
authors.affiliation: Institute for Rare and Neglected Diseases Drug Discovery, Mountain View, CA, USA.
authors.forename: David C
authors.initials: DC
authors.lastname: Swinney
mesh_terms: D047228:Angiotensin II Type 1 Receptor Blockers / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D001665:Binding Sites / Q000187:drug effects; D006801:Humans; D008024:Ligands; D044140:Receptor, Angiotensin, Type 1 / Q000378:metabolism*
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers; D008024:Ligands; D044140:Receptor, Angiotensin, Type 1