Using Molecular Initiating Events to Develop a Structural Alert Based Screening Workflow for Nuclear Receptor Ligands Associated with Hepatic Steatosis

Chemical Research in Toxicology
Claire L MellorMark T D Cronin

Abstract

In silico models are essential for the development of integrated alternative methods to identify organ level toxicity and lead toward the replacement of animal testing. These models include (quantitative) structure-activity relationships ((Q)SARs) and, importantly, the identification of structural alerts associated with defined toxicological end points. Structural alerts are able both to predict toxicity directly and assist in the formation of categories to facilitate read-across. They are particularly important to decipher the myriad mechanisms of action that result in organ level toxicity. The aim of this study was to develop novel structural alerts for nuclear receptor (NR) ligands that are associated with inducing hepatic steatosis and to show the vast number of existing data that are available. Current knowledge on NR agonists was extended with data from the ChEMBL database (12,713 chemicals in total) of bioactive molecules and from studying NR ligand-binding interactions within the protein database (PDB, 624 human NR structure files). A computational structural alert based workflow was developed using KNIME from these data using molecular fragments and other relevant chemical features. In total, 214 structural features we...Continue Reading

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Citations

Apr 1, 2017·Chemical Research in Toxicology·Thomas HartungShana J Sturla
Oct 16, 2016·SLAS Technology·Martin AdamKerstin Thurow
Jan 18, 2018·Journal of Cheminformatics·Samina Kausar, Andre O Falcao
Apr 23, 2019·Journal of Applied Toxicology : JAT·Xueyan CuiXiao Li
Apr 27, 2020·Environmental Toxicology and Chemistry·Claire L MellorJames W Firman
May 20, 2020·Archives of Toxicology·Nicoleta SpinuAndrew P Worth
Jul 27, 2017·Toxicological Research·Mark T D CroninJudith C Madden
May 19, 2020·Toxicology and Environmental Health Sciences·Kyung-Taek Rim
Dec 15, 2020·Chemical Research in Toxicology·James W FirmanMark T D Cronin
Sep 25, 2018·Computational Toxicology·Jeremy A LeonardYu-Mei Tan
Apr 10, 2019·Current Medicinal Chemistry·Michael P MazanetzEwa I Chudyk
Mar 14, 2020·Chemical Research in Toxicology·Jakub Kostal, Adelina Voutchkova-Kostal
Dec 10, 2020·Chemical Research in Toxicology·Andrew J WedlakePaul J Russell
Nov 21, 2020·Chemical Research in Toxicology·Johanna Krebs, Maureen McKeague
Dec 8, 2017·Computational Toxicology·Elisabet BerggrenCatherine Mahony

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