'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.
Abbreviations[L], concentration of ligand in bulk of solution; RL and R'L, loose and tight binding ligand-receptor complexes; △G o , difference in Gibbs free energy between R and R'L; k 1 , k 2 … k 1A … k 1M …, microscopic rate constants; k obs , k on , k off , macroscopic rate constants for association and dissociation; K D , 'thermodynamic' equilibrium dissociation constant based on △G o ; K D *, [L] at which this observed binding is half-maximal at equilibrium; app K D *, [L] at which the observed binding is half-maximal under earlier non-equilibrium conditions; p, -LogThese Tables list key protein targets and ligands in this article which are hyperlinked to corresponding entries in http://www.guidetopharmacology. org, the common portal for data from the IUPHAR/BPS Guide to PHARMACOLOGY (Pawson et al., 2014) and are permanently archived in the Concise Guide to PHARMACOLOGY 2015/16 (Alexander et al., 2015.