Abstract
Since 2009, the Tox21 project has screened ∼8500 chemicals in more than 70 high-throughput assays, generating upward of 100 million data points, with all data publicly available through partner websites at the United States Environmental Protection Agency (EPA), National Center for Advancing Translational Sciences (NCATS), and National Toxicology Program (NTP). Underpinning this public effort is the largest compound library ever constructed specifically for improving understanding of the chemical basis of toxicity across research and regulatory domains. Each Tox21 federal partner brought specialized resources and capabilities to the partnership, including three approximately equal-sized compound libraries. All Tox21 data generated to date have resulted from a confluence of ideas, technologies, and expertise used to design, screen, and analyze the Tox21 10K library. The different programmatic objectives of the partners led to three distinct, overlapping compound libraries that, when combined, not only covered a diversity of chemical structures, use-categories, and properties but also incorporated many types of compound replicates. The history of development of the Tox21 “10K” chemical library and data workflows implemented to ensure quality chemical annotations and allow for various reproducibility assessments are described. Cheminformatics profiling demonstrates how the three partner libraries complement one another to expand the reach of each individual library, as reflected in coverage of regulatory lists, predicted toxicity end points, and physicochemical properties. ToxPrint chemotypes (CTs) and enrichment approaches further demonstrate how the combined partner libraries amplify structure–activity patterns that would otherwise not be detected. Finally, CT enrichments are used to probe global patterns of activity in combined ToxCast and Tox21 activity data sets relative to test-set size and chemical versus biological end point diversity, illustrating the power of CT approaches to discern patterns in chemical–activity data sets. These results support a central premise of the Tox21 program: A collaborative merging of programmatically distinct compound libraries would yield greater rewards than could be achieved separately.
Highlights
Prior to 2004, the construction and high-throughput screening (HTS) of compound libraries were primarily the domain of the pharmaceutical industry, directed toward the goal of identifying candidates for drug development that interact and with high potency, with a wide range of putative therapeutic targets
The Molecular Libraries Initiative (MLI) led to the creation of the National Institutes of Health (NIH) Molecular Libraries Small Molecule Repository (MLSMR), a compound library of >300 K substances procured from commercial sources
Recognizing the necessity of an informatics support infrastructure, the program included the creation of PubChem, a public, structure-centric, cheminformatics platform whose initial mandate was to serve as the public repository for all chemical structures and HTS data generated by the MLI program.[4,5]
Summary
Prior to 2004, the construction and high-throughput screening (HTS) of compound libraries were primarily the domain of the pharmaceutical industry, directed toward the goal of identifying candidates for drug development that interact and with high potency, with a wide range of putative therapeutic targets. The Tox[21] Program was formally launched in 2008 as a collaboration among these three federal partners EPA, NTP, and NCGC/NCATS with the United States Food and Drug Administration (FDA) joining the partnership in 2010.10−12 (Note: For purposes of this report, we will use the label NCATS to encompass both organizational periods, that is, NCGC until 2012 and NCATS after 2012.) The stated goals of the program included: research, development, validation, and translation of innovative compound testing methods to characterize toxicity pathways, prioritizing compounds for more extensive toxicological evaluation, and developing predictive models for biological response in humans and the environment To help achieve these goals, the Tox[21] partners created a compound library of ∼10,000 agency-relevant chemical samples to be screened in a battery of quantitative HTS (qHTS) assays at the NCATS intramural robotics facility.[13] Testing initially focused on a broad set of assays associated with nuclear receptor activities and stress pathways. This first in the series of Tox[21] compound library papers is intended to inform and guide current application and analysis of Tox[21] data as well as future compound screening, assay interpretation, and predictive modeling activities in toxicology
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