Using 2D Structural Alerts to Define Chemical Categories for Molecular Initiating Events.
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Publication Date
2018-09-01Journal Title
Toxicol Sci
ISSN
1096-6080
Publisher
Oxford University Press (OUP)
Volume
165
Issue
1
Pages
213-223
Language
eng
Type
Article
Physical Medium
Print
Metadata
Show full item recordCitation
Allen, T., Goodman, J., Gutsell, S., & Russell, P. J. (2018). Using 2D Structural Alerts to Define Chemical Categories for Molecular Initiating Events.. Toxicol Sci, 165 (1), 213-223. https://doi.org/10.1093/toxsci/kfy144
Abstract
Molecular initiating events (MIEs) are important concepts for in silico predictions. They can be used to link chemical characteristics to biological activity through an adverse outcome pathway (AOP). In this work, we capture chemical characteristics in 2D structural alerts, which are then used as models to predict MIEs. An automated procedure has been used to identify these alerts, and the chemical categories they define have been used to provide quantitative predictions for the activity of molecules that contain them. This has been done across a diverse group of 39 important pharmacological human targets using open source data. The alerts for each target combine into a model for that target, and these models are joined into a tool for MIE prediction with high average model performance (sensitivity = 82%, specificity = 93%, overall quality = 93%, Matthews correlation coefficient = 0.57). The result is substantially improved from our previous study (Allen, T. E. H., Goodman, J. M., Gutsell, S., and Russell, P. J. 2016. A history of the molecular initiating event. Chem. Res. Toxicol. 29, 2060-2070) for which the mean sensitivity for each target was only 58%. This tool provides the first step in an AOP-based risk assessment, linking chemical structure to toxicity endpoint.
Keywords
Humans, Pharmaceutical Preparations, Risk Assessment, Molecular Structure, Structure-Activity Relationship, Computer Simulation, Databases, Pharmaceutical, Adverse Outcome Pathways
Sponsorship
Unilever
Identifiers
External DOI: https://doi.org/10.1093/toxsci/kfy144
This record's URL: https://www.repository.cam.ac.uk/handle/1810/279614
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