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Estimation of competitive antagonist affinity by the Schild method and from functional inhibition curves using a novel form of the Gaddum equation
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SYSNO ASEP 0505342 Druh ASEP J - Článek v odborném periodiku Zařazení RIV J - Článek v odborném periodiku Poddruh J Článek ve WOS Název Estimation of competitive antagonist affinity by the Schild method and from functional inhibition curves using a novel form of the Gaddum equation Tvůrce(i) Ezechiáš, Martin (MBU-M) RID
Cajthaml, Tomáš (MBU-M) RID, ORCIDZdroj.dok. Toxicology. - : Elsevier - ISSN 0300-483X
Roč. 420, 15 MAY (2019), s. 21-28Poč.str. 8 s. Jazyk dok. eng - angličtina Země vyd. IE - Irsko Klíč. slova Receptor theory ; Equilibrium constant ; Gaddum equation Vědní obor RIV FP - Ostatní lékařské obory Obor OECD Toxicology CEP GJ17-15678Y GA ČR - Grantová agentura ČR Způsob publikování Omezený přístup Institucionální podpora MBU-M - RVO:61388971 UT WOS 000468707800004 EID SCOPUS 85063763246 DOI 10.1016/j.tox.2019.03.015 Anotace The equilibrium dissociation constant of competitive antagonists represents the affinity of the receptor-ligand interaction, and it is a key characteristic of many therapeutic drugs or toxic compounds. Two commonly used methods by which the affinity of the antagonist can be estimated are Schild analysis and the Cheng-Prusoff method. However, both methods yield different results when applied to systems with slopes not equal to one. The Gaddum equation, which is fundamental for both methods, should be extended to incorporate the slope parameter of the dose-response curves and this extension should diminish the differences between the Schild and Cheng-Prusoff methods. In this study, we derived a novel form of the Gaddum equation with a slope parameter (Hill coefficient) of agonist dose-response curve. We also derived the subsequent equations for Schild and Cheng-Prusoff analysis and we validated the proposed model by the measurement of several known estrogen receptor competitive antagonists. Standardized in vitro yeast reporter gene assay (BMAEREluc/ER alpha) has been used for the measurements and the range of used antagonist concentrations was 1.37-46.03 mu M. By applying our mathematical model, both Schild and Cheng-Prusoff methods provide more similar values of antagonist affinity than the original mathematical approach. The correctness of the model has also been demonstrated by the measurement of a partial agonist with a known receptor affinity. The presented mathematical model significantly reduces the differences in values calculated by the Cheng-Prusoff and Schild methods and yields more accurate estimations of antagonist affinity. Pracoviště Mikrobiologický ústav Kontakt Eliška Spurná, eliska.spurna@biomed.cas.cz, Tel.: 241 062 231 Rok sběru 2020 Elektronická adresa https://www.sciencedirect.com/science/article/pii/S0300483X18307285?via%3Dihub
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