Applications and limitations of fitting of the operational model to determine relative efficacies of agonists

Kód výsledku v IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F67985823%3A_____%2F19%3A00504453" target="_blank" >RIV/67985823:_____/19:00504453 - isvavai.cz</a>

Výsledek na webu

<a href="https://doi.org/10.1038/s41598-019-40993-w" target="_blank" >https://doi.org/10.1038/s41598-019-40993-w</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1038/s41598-019-40993-w" target="_blank" >10.1038/s41598-019-40993-w</a>

Jazyk výsledku

angličtina

Název v původním jazyce

Applications and limitations of fitting of the operational model to determine relative efficacies of agonists

Popis výsledku v původním jazyce

Proper determination of agonist efficacy is essential in the assessment of agonist selectivity and signalling bias. Agonist efficacy is a relative term that is dependent on the system in which it is measured, especially being dependent on receptor expression level. The operational model (OM) of functional receptor agonism is a useful means for the determination of agonist functional efficacy using the maximal response to agonist and ratio of agonist functional potency to its equilibrium dissociation constant (KA) at the active state of the receptor. However, the functional efficacy parameter tau is interdependent on two other parameters of OM, agonist's KA and the highest response that could be evoked in the system by any stimulus (EMAX). Thus, fitting of OM to functional response data is a tricky process. In this work we analyse pitfalls of fitting OM to experimental data and propose a rigorous fitting procedure where KA and EMAX are derived from half-efficient concentration of agonist and apparent maximal responses obtained from a series of functional response curves. Subsequently, OM with fixed KA and EMAX is fitted to functional response data to obtain tau.

Název v anglickém jazyce

Applications and limitations of fitting of the operational model to determine relative efficacies of agonists

Popis výsledku anglicky

Proper determination of agonist efficacy is essential in the assessment of agonist selectivity and signalling bias. Agonist efficacy is a relative term that is dependent on the system in which it is measured, especially being dependent on receptor expression level. The operational model (OM) of functional receptor agonism is a useful means for the determination of agonist functional efficacy using the maximal response to agonist and ratio of agonist functional potency to its equilibrium dissociation constant (KA) at the active state of the receptor. However, the functional efficacy parameter tau is interdependent on two other parameters of OM, agonist's KA and the highest response that could be evoked in the system by any stimulus (EMAX). Thus, fitting of OM to functional response data is a tricky process. In this work we analyse pitfalls of fitting OM to experimental data and propose a rigorous fitting procedure where KA and EMAX are derived from half-efficient concentration of agonist and apparent maximal responses obtained from a series of functional response curves. Subsequently, OM with fixed KA and EMAX is fitted to functional response data to obtain tau.

Druh

J_imp - Článek v periodiku v databázi Web of Science

CEP obor

—

OECD FORD obor

30105 - Physiology (including cytology)

Projekt

<a href="/cs/project/GA17-16182S" target="_blank" >GA17-16182S: Molekulární základy funkční selektivity solí N-subtituovaného tetrahydropyridinia na muskarinových receptorech</a><br>

Návaznosti

I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace

Rok uplatnění

2019

Kód důvěrnosti údajů

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Název periodika

Scientific Reports

ISSN

2045-2322

e-ISSN

—

Svazek periodika

9

Číslo periodika v rámci svazku

Mar 15

Stát vydavatele periodika

GB - Spojené království Velké Británie a Severního Irska

Počet stran výsledku

14

Strana od-do

4637

Kód UT WoS článku

000461303000019

EID výsledku v databázi Scopus

2-s2.0-85063014966