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Validation of a fragment-based profiler for thiol reactivity for the prediction of toxicity: skin sensitisation and tetrahymena pyriformis

Ebbrell, DJ, Madden, JC, Cronin, MTD, Schultz, TW and Enoch, SJ (2017) Validation of a fragment-based profiler for thiol reactivity for the prediction of toxicity: skin sensitisation and tetrahymena pyriformis. Chemical Research in Toxicology, 30 (2). pp. 604-613. ISSN 0893-228X

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This study outlines the use of a recently developed fragment-based thiol reactivity profiler for Michael acceptors to predict toxicity towards Tetrahymena pyriformis and skin sensitisation potency as determined in the Local Lymph Node Assay (LLNA). The results showed that the calculated reactivity parameter from the profiler, -log RC50(calc), was capable of predicting toxicity for both endpoints with excellent statistics. However, the study highlighted the importance of a well-defined applicability domain for each endpoint. In terms of Tetrahymena pyriformis this domain was defined in terms of how fast or slowly a given Michael acceptor reacts with thiol leading to two separate quantitative structure-activity models. The first, for fast reacting chemicals required only –Log RC50(calc) as a descriptor, whilst the second required the addition of a descriptor for hydrophobicity. Modelling of the LLNA required only a single descriptor, -log RC50(calc), enabling potency to be predicted. The applicability domain excluded chemicals capable of undergoing polymerisation and those that were predicted to be volatile. The modelling results for both endpoints, using the –log RC50(calc) value from the profiler, were in keeping with previously published studies that have utilised experimentally determined measurements of reactivity. This results demonstrate the output from the fragment-based thiol reactivity profiler can be used to develop quantitative structure-activity relationship models where reactivity towards thiol is a driver of toxicity.

Item Type: Article
Uncontrolled Keywords: 0302 Inorganic Chemistry, 0304 Medicinal And Biomolecular Chemistry, 0305 Organic Chemistry
Subjects: R Medicine > RM Therapeutics. Pharmacology
Divisions: Pharmacy & Biomolecular Sciences
Publisher: American Chemical Society
Date Deposited: 09 Jan 2017 11:42
Last Modified: 04 Sep 2021 12:08
DOI or ID number: 10.1021/acs.chemrestox.6b00361
URI: https://researchonline.ljmu.ac.uk/id/eprint/5201
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