Background And Purpose: Target engagement dynamics can influence drugs' pharmacological effects. Kinetic parameters for drug:target interactions are often quantified by evaluating competition association experiments-measuring simultaneous protein binding of labelled tracers and unlabelled test compounds over time-with Motulsky-Mahan's "kinetics of competitive binding" model. Despite recent technical improvements, the current assay formats impose practical limitations to this approach. This study aims at the characterisation, understanding and prevention of these experimental constraints, and associated analytical challenges.
Experimental Approach: Monte Carlo simulations were used to run virtual kinetic and equilibrium tracer binding and competition experiments in both normal and perturbed assay conditions. Data were fitted to standard equations derived from the mass action law (including Motulsky-Mahan's) and to extended versions aiming to cope with frequently observed deviations of the canonical traces. Results were compared to assess the precision and accuracy of these models and identify experimental factors influencing their performance.
Key Results: Key factors influencing the precision and accuracy of the Motulsky-Mahan model are the interplay between compound dissociation rates, measurement time and interval frequency, tracer concentration and binding kinetics and the relative abundance of equilibrium complexes in vehicle controls. Experimental results produced recommendations for better design of tracer characterisation experiments and new strategies to deal with systematic signal decay.
Conclusions And Implications: Our data advances our comprehension of the Motulsky-Mahan kinetics of competitive binding models and provides experimental design recommendations, data analysis tools, and general guidelines for its practical application to in vitro pharmacology and drug screening.
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http://dx.doi.org/10.1111/bph.14841 | DOI Listing |
Anal Chim Acta
February 2025
School of Chemistry and Chemical Engineering, University of Jinan, Jinan, 250022, PR China; Department of Chemistry, Sungkyunkwan University, Suwon, 16419, Republic of Korea. Electronic address:
Background: Estriol (E3) is a common estrogen responsible for regulating the female reproductive system, but excessive amount can pose health risks to humans and wild life. Therefore, sensitive and accurate detection of estriol level is crucial. A novel competitive ECL immunosensor based on a dual signal amplification strategy of AuNPs@GO@SmMoSe and Gd(MoO) was fabricated for ultrasensitive detection of estriol.
View Article and Find Full Text PDFGenomics
January 2025
Department of General Surgery, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou 510630, China. Electronic address:
Introduction: Resistance to lenvatinib limits the effectiveness of the targeted treatments for HCC. However, the exact mechanism behind this resistance remains elusive. Current research suggests that circular RNA (circRNA) is pivotal in mediating drug resistance during targeted treatments.
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Department of Pediatrics and Adolescent Medicine, University Hospital Erlangen, Erlangen, Germany; Comprehensive Cancer Center Erlangen-EMN (CCC ER-EMN), Erlangen, Germany; Bavarian Cancer Research Center (BZKF), Erlangen, Germany. Electronic address:
Achieving a stable deep molecular response with the option to discontinue tyrosine kinase inhibitors (TKI) treatment is the new therapeutic goal for patients with chronic myeloid leukemia (CML). Several studies have shown that individuals expressing the BCR::ABL1 e14a2 transcript achieve a major molecular response more rapidly than those with the e13a2 transcript. However, technical issues may have confounded these observations, and data for pediatric patients are limited.
View Article and Find Full Text PDFJ Hazard Mater
January 2025
Laboratory of Environmental Toxicology, Chulabhorn Research Institute, Bangkok 10210, Thailand; Center of Excellence on Environmental Health and Toxicology (EHT), OPS, Ministry of Higher Education, Science, Research and Innovation, Bangkok, Thailand. Electronic address:
2-Ethylhexyl diphenyl phosphate (EHDPP) is a replacement flame-retardant commonly found in several environmental matrices and human biospecimens. Although some adverse effects of EHDPP have been identified, the endocrine-disrupting effects of EHDPP and its key metabolites on the human estrogen receptor (ER) are largely unknown. Herein, we report for the first time that EHDPP, at concentrations found in the environment and humans, significantly promoted estrogenic activity and synergized with 17β-estradiol-induced ER transactivation.
View Article and Find Full Text PDFCortex
December 2024
Humboldt-Universität zu Berlin, Berlin School of Mind and Brain, Berlin, Germany; Max Planck Institute for Human Cognitive and Brain Sciences, Department of Neurology, Leipzig, Germany; University Hospital and Faculty of Medicine Leipzig, Clinic for Cognitive Neurology, Leipzig, Germany.
Retrieving words quickly and correctly is an important language competence. Semantic contexts, such as prior naming of categorically related objects, can induce conceptual priming but also lexical-semantic interference, the latter likely due to enhanced competition during lexical selection. In the continuous naming (CN) paradigm, such semantic interference is evident in a linear increase in naming latency with each additional member of a category out of a seemingly random sequence of pictures being named (cumulative semantic interference/CSI effect).
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