Analysis of equilibrium binding of an orthosteric tracer and two allosteric modulators

Jan Jakubík, Alena Randáková, Esam E. El-Fakahany, Vladimír Doležal

Research output: Contribution to journalArticle

Abstract

Allosteric ligands bind to receptors at sites that are distinct from those endogenous agonists and orthosteric pharmacological agents interact with. Both an allosteric and orthosteric ligand bind simultaneously to the receptor to form a ternary complex, where each ligand influences binding affinity of the other to the receptor, either positively or negatively. Allosteric modulators are an intensively studied group of receptor ligands because of their potentially greater selectivity over orthosteric ligands, with the possibility of fine tuning of the effects of endogenous neurotransmitters and hormones. The affinity of an unlabelled allosteric ligand is commonly estimated by measuring its effects on binding of a radio-labelled orthosteric tracer. This scenario is complicated by many folds when one studies the kinetics of interactions of two allosteric agents, added simultaneously, on binding of an orthosteric tracer. In this paper, we provide, for the first time, theoretical basis for analysis of such complex interactions. We have expanded our analysis to include the possibility of having two allosteric modulators interact with the same or different sites on the receptor. An added value of our analysis is to provide a tool to distinguish between the two situations. Finally, we also modelled binding of two molecules of one allosteric modulator to one receptor.

Original languageEnglish (US)
Article numbere0214255
JournalPloS one
Volume14
Issue number3
DOIs
StatePublished - Mar 2019

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Modulators
tracer techniques
Ligands
receptors
value added
neurotransmitters
Radio
radio
agonists
Neurotransmitter Agents
ligands
Tuning
hormones
Hormones
Pharmacology
kinetics
Molecules
Kinetics

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Analysis of equilibrium binding of an orthosteric tracer and two allosteric modulators. / Jakubík, Jan; Randáková, Alena; El-Fakahany, Esam E.; Doležal, Vladimír.

In: PloS one, Vol. 14, No. 3, e0214255, 03.2019.

Research output: Contribution to journalArticle

Jakubík, Jan ; Randáková, Alena ; El-Fakahany, Esam E. ; Doležal, Vladimír. / Analysis of equilibrium binding of an orthosteric tracer and two allosteric modulators. In: PloS one. 2019 ; Vol. 14, No. 3.
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