Show simple item record

dc.contributor.authorAllen, Timothy
dc.contributor.authorGoodman, Jonathan
dc.contributor.authorGutsell, Steve
dc.contributor.authorRussell, Paul J
dc.date.accessioned2018-09-05T12:50:11Z
dc.date.available2018-09-05T12:50:11Z
dc.date.issued2018-09-01
dc.identifier.issn1096-6080
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/279614
dc.description.abstractMolecular 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.
dc.description.sponsorshipUnilever
dc.format.mediumPrint
dc.languageeng
dc.publisherOxford University Press (OUP)
dc.subjectHumans
dc.subjectPharmaceutical Preparations
dc.subjectRisk Assessment
dc.subjectMolecular Structure
dc.subjectStructure-Activity Relationship
dc.subjectComputer Simulation
dc.subjectDatabases, Pharmaceutical
dc.subjectAdverse Outcome Pathways
dc.titleUsing 2D Structural Alerts to Define Chemical Categories for Molecular Initiating Events.
dc.typeArticle
prism.endingPage223
prism.issueIdentifier1
prism.publicationDate2018
prism.publicationNameToxicol Sci
prism.startingPage213
prism.volume165
dc.identifier.doi10.17863/CAM.26985
dcterms.dateAccepted2018-06-01
rioxxterms.versionofrecord10.1093/toxsci/kfy144
rioxxterms.licenseref.urihttp://www.rioxx.net/licenses/all-rights-reserved
rioxxterms.licenseref.startdate2018-09
dc.contributor.orcidAllen, Timothy [0000-0001-7369-0901]
dc.contributor.orcidGoodman, Jonathan [0000-0002-8693-9136]
dc.identifier.eissn1096-0929
rioxxterms.typeJournal Article/Review
cam.issuedOnline2018-07-18
rioxxterms.freetoread.startdate2019-07-18


Files in this item

Thumbnail

This item appears in the following Collection(s)

Show simple item record