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

Mellor, CL and Steinmetz, FP and Cronin, MTD (2016) Using Molecular Initiating Events to Develop a Structural Alert Based Screening Workflow for Nuclear Receptor Ligands Associated with Hepatic Steatosis. Chemical Research in Toxicology, 29 (2). pp. 203-212. ISSN 1520-5010

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Abstract

In silico models are essential for the development of integrated alternative methods to identify organ level toxicity and lead towards 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 endpoints. 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 data base (PBD, 624 human NR structure files). A computational structural alerts based workflow was developed using KNIME from these data using molecular fragments and other relevant chemical features. In total 214 structural features were recorded computationally as SMARTS strings and, therefore, they can be used for grouping and screening during drug development and hazard assessment and provide knowledge to anchor adverse outcome pathways (AOPs) via their molecular initiating events (MIEs).

Item Type: Article
Uncontrolled Keywords: 0302 Inorganic Chemistry, 0304 Medicinal And Biomolecular Chemistry, 0305 Organic Chemistry
Subjects: Q Science > QD Chemistry
R Medicine > RS Pharmacy and materia medica
Divisions: Pharmacy & Biomolecular Sciences
Publisher: American Chemical Society
Date Deposited: 02 Feb 2016 11:32
Last Modified: 19 Jan 2017 00:50
DOI or Identification number: 10.1021/acs.chemrestox.5b00480
URI: http://researchonline.ljmu.ac.uk/id/eprint/2807

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