A critical re-evaluation of the slope factor of the operational model of agonism: When to exponentiate operational efficacy
Abstract Agonist efficacy denoting the “strength” of agonist action is a cornerstone in the proper assessment of agonist selectivity and signalling bias. The simulation models are very accurate but complex and hard to fit experimental data. The parsimonious operational model of agonism (OMA) has bec...
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2023-10-01
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| Series: | Scientific Reports |
| Online Access: | https://doi.org/10.1038/s41598-023-45004-7 |
| _version_ | 1827634962927452160 |
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| author | Alena Randáková Dominik Nelic Jan Jakubík |
| author_facet | Alena Randáková Dominik Nelic Jan Jakubík |
| author_sort | Alena Randáková |
| collection | DOAJ |
| description | Abstract Agonist efficacy denoting the “strength” of agonist action is a cornerstone in the proper assessment of agonist selectivity and signalling bias. The simulation models are very accurate but complex and hard to fit experimental data. The parsimonious operational model of agonism (OMA) has become successful in the determination of agonist efficacies and ranking them. In 1983, Black and Leff introduced the slope factor to the OMA to make it more flexible and allow for fitting steep as well as flat concentration–response curves. First, we performed a functional analysis to indicate the potential pitfalls of the OMA. Namely, exponentiation of operational efficacy may break relationships among the OMA parameters. The fitting of the Black & Leff equation to the theoretical curves of several models of functional responses and the experimental data confirmed the fickleness of the exponentiation of operational efficacy affecting estimates of operational efficacy as well as other OMA parameters. In contrast, fitting The OMA based on the Hill equation to the same data led to better estimates of model parameters. In conclusion, Hill equation-based OMA should be preferred over the Black & Leff equation when functional-response curves differ in the slope factor. Otherwise, the Black & Leff equation should be used with extreme caution acknowledging potential pitfalls. |
| first_indexed | 2024-03-09T15:20:40Z |
| format | Article |
| id | doaj.art-93e657224a974635a025309073addb3d |
| institution | Directory Open Access Journal |
| issn | 2045-2322 |
| language | English |
| last_indexed | 2024-03-09T15:20:40Z |
| publishDate | 2023-10-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Scientific Reports |
| spelling | doaj.art-93e657224a974635a025309073addb3d2023-11-26T12:49:44ZengNature PortfolioScientific Reports2045-23222023-10-0113111510.1038/s41598-023-45004-7A critical re-evaluation of the slope factor of the operational model of agonism: When to exponentiate operational efficacyAlena Randáková0Dominik Nelic1Jan Jakubík2Institute of Physiology Czech Academy of SciencesInstitute of Physiology Czech Academy of SciencesInstitute of Physiology Czech Academy of SciencesAbstract Agonist efficacy denoting the “strength” of agonist action is a cornerstone in the proper assessment of agonist selectivity and signalling bias. The simulation models are very accurate but complex and hard to fit experimental data. The parsimonious operational model of agonism (OMA) has become successful in the determination of agonist efficacies and ranking them. In 1983, Black and Leff introduced the slope factor to the OMA to make it more flexible and allow for fitting steep as well as flat concentration–response curves. First, we performed a functional analysis to indicate the potential pitfalls of the OMA. Namely, exponentiation of operational efficacy may break relationships among the OMA parameters. The fitting of the Black & Leff equation to the theoretical curves of several models of functional responses and the experimental data confirmed the fickleness of the exponentiation of operational efficacy affecting estimates of operational efficacy as well as other OMA parameters. In contrast, fitting The OMA based on the Hill equation to the same data led to better estimates of model parameters. In conclusion, Hill equation-based OMA should be preferred over the Black & Leff equation when functional-response curves differ in the slope factor. Otherwise, the Black & Leff equation should be used with extreme caution acknowledging potential pitfalls.https://doi.org/10.1038/s41598-023-45004-7 |
| spellingShingle | Alena Randáková Dominik Nelic Jan Jakubík A critical re-evaluation of the slope factor of the operational model of agonism: When to exponentiate operational efficacy Scientific Reports |
| title | A critical re-evaluation of the slope factor of the operational model of agonism: When to exponentiate operational efficacy |
| title_full | A critical re-evaluation of the slope factor of the operational model of agonism: When to exponentiate operational efficacy |
| title_fullStr | A critical re-evaluation of the slope factor of the operational model of agonism: When to exponentiate operational efficacy |
| title_full_unstemmed | A critical re-evaluation of the slope factor of the operational model of agonism: When to exponentiate operational efficacy |
| title_short | A critical re-evaluation of the slope factor of the operational model of agonism: When to exponentiate operational efficacy |
| title_sort | critical re evaluation of the slope factor of the operational model of agonism when to exponentiate operational efficacy |
| url | https://doi.org/10.1038/s41598-023-45004-7 |
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