On the different experimental manifestations of two-state 'induced-fit' binding of drugs to their cellular targets

British Journal of Pharmacology
Georges VauquelinDavid C Swinney

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 pre...Continue Reading

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Citations

Apr 30, 2016·British Journal of Pharmacology·Georges Vauquelin
Jun 24, 2017·ACS Chemical Neuroscience·Peter J Tonge
Feb 28, 2018·British Journal of Pharmacology·Dong GuoAdriaan P IJzerman
Aug 25, 2017·British Journal of Pharmacology·Georges Vauquelin
Nov 7, 2020·Trends in Pharmacological Sciences·Georges VauquelinDavid C Swinney
May 18, 2018·Journal of Medicinal Chemistry·John G QuinnMelinda M Mulvihill
Aug 31, 2021·Pharmacology Research & Perspectives·Georges Vauquelin, Dominique Maes
Jul 3, 2021·Expert Opinion on Drug Discovery·Robert A Copeland

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