Prediction of organ toxicity endpoints by QSAR modeling based on precise chemical-histopathology annotations

Chemical Biology & Drug Design
Eugene MyshkinSvetlana Bureeva

Abstract

The ability to accurately predict the toxicity of drug candidates from their chemical structure is critical for guiding experimental drug discovery toward safer medicines. Under the guidance of the MetaTox consortium (Thomson Reuters, CA, USA), which comprised toxicologists from the pharmaceutical industry and government agencies, we created a comprehensive ontology of toxic pathologies for 19 organs, classifying pathology terms by pathology type and functional organ substructure. By manual annotation of full-text research articles, the ontology was populated with chemical compounds causing specific histopathologies. Annotated compound-toxicity associations defined histologically from rat and mouse experiments were used to build quantitative structure-activity relationship models predicting subcategories of liver and kidney toxicity: liver necrosis, liver relative weight gain, liver lipid accumulation, nephron injury, kidney relative weight gain, and kidney necrosis. All models were validated using two independent test sets and demonstrated overall good performance: initial validation showed 0.80-0.96 sensitivity (correctly predicted toxic compounds) and 0.85-1.00 specificity (correctly predicted non-toxic compounds). Later val...Continue Reading

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Citations

Feb 1, 2014·Computers in Biology and Medicine·Andrey A ToropovJerzy Leszczynski
Dec 24, 2013·Journal of Pharmacological and Toxicological Methods·Sean Ekins
Dec 3, 2014·Expert Opinion on Drug Metabolism & Toxicology·Vinícius Gonçalves MaltarolloKathia Maria Honorio
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Feb 26, 2016·Chemical Research in Toxicology·Denis MullinerAlexander Amberg
Nov 2, 2017·Expert Opinion on Drug Discovery·Carolina L BelleraAlan Talevi
Oct 23, 2018·Expert Opinion on Drug Metabolism & Toxicology·Julia PletzMark T D Cronin
Jan 17, 2019·Toxicological Sciences : an Official Journal of the Society of Toxicology·Susanne RammVishal S Vaidya
May 11, 2019·Expert Opinion on Drug Discovery·Carolina L Bellera, Alan Talevi
Oct 12, 2018·Journal of Cheminformatics·Alexander KensertOla Spjuth

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