Citation:

Richard, A., R. Huang, S. Waidyanatha, P. Shinn, B. Collins, I. Thillainadarajah, Chris Grulke, A. Williams, R. Lougee, R. Judson, K. Houck, Mahmoud A. Shobair, C. Yang, J. Rathman, A. Yasgar, S. Fitzpatrick, A. Simeonov, R. Thomas, K. Crofton, R. Paules, J. Bucher, C. Austin, R. Kavlock, AND R. Tice. The Tox21 10K Compound Library: Collaborative Chemistry Advancing Toxicology. CHEMICAL RESEARCH IN TOXICOLOGY. American Chemical Society, Washington, DC, 34(2):189-216, (2021). https://doi.org/10.1021/acs.chemrestox.0c00264

Impact/Purpose:

Over the past decade, the cross-federal agency Tox21 project has screened approximately 8500 chemicals in approximately 70 high-throughput assays, generating upwards of 100 million data points for over 200 endpoint readouts, with all data publicly available through partner-websites across the U.S. Environmental Protection Agency (EPA) and the National Institutes of Health’s National Center for Advancing Translational Sciences (NCATS) and National Toxicology Program (NTP). Underpinning and fueling this effort has been the largest compound library constructed specifically for the purpose of improving understanding of the chemical-basis of toxicity and spanning several areas of regulatory authority and applications (e.g., pharmaceuticals, environmental chemicals, food additives, consumer products). Each Tox21 federal partner has brought specialized resources and capabilities to the partnership, including three separately sourced and approximately equal sized compound libraries from the original partners (NCATS, NTP, EPA). The unique confluence of libraries, ideas, technologies and expertise to create, manage, screen, and analyze the Tox21 10K library has yielded a wealth of chemical-bioactivity data and new opportunities for researchers to use and analyze these data. The development of the Tox21 “10K” chemical library and data workflows put in place to ensure high quality results are described. Tox21 partner library contributions are then compared through several property and structural lenses, including regulatory and usage lists, predicted toxicity endpoints, physicochemical properties, and molecular features. ToxPrint chemotypes (CTs) and CT-enrichment approaches are used to compare the partner libraries and their contributions to differential structure-activity patterns between the NCATS drug library and the EPA and NTP libraries combined, the latter representing environmental chemicals. Finally, CT-enrichments are used to probe global patterns of activity, illuminating relative influences of test-set size and chemical versus biological space diversity on enrichment results. The results illustrate the power of CT-enrichment approaches to guide and inform future analysis of Tox21 chemical-activity datasets.

Description:

Over the past decade, the cross-federal agency Tox21 project has screened approximately 8500 chemicals in approximately 70 high-throughput assays, generating upwards of 100 million data points for over 200 endpoint readouts, with all data publicly available through partner-websites across the U.S. Environmental Protection Agency (EPA) and the National Institutes of Health’s National Center for Advancing Translational Sciences (NCATS) and National Toxicology Program (NTP). Underpinning and fueling this effort has been the largest compound library constructed specifically for the purpose of improving understanding of the chemical-basis of toxicity and spanning several areas of regulatory authority and applications (e.g., pharmaceuticals, environmental chemicals, food additives, consumer products). Each Tox21 federal partner has brought specialized resources and capabilities to the partnership, including three separately sourced and approximately equal sized compound libraries from the original partners (NCATS, NTP, EPA). The unique confluence of libraries, ideas, technologies and expertise to create, manage, screen, and analyze the Tox21 10K library has yielded a wealth of chemical-bioactivity data and new opportunities for researchers to use and analyze these data. The development of the Tox21 “10K” chemical library and data workflows put in place to ensure high quality results are described. Tox21 partner library contributions are then compared through several property and structural lenses, including regulatory and usage lists, predicted toxicity endpoints, physicochemical properties, and molecular features. ToxPrint chemotypes (CTs) and CT-enrichment approaches are used to compare the partner libraries and their contributions to differential structure-activity patterns between the NCATS drug library and the EPA and NTP libraries combined, the latter representing environmental chemicals. Finally, CT-enrichments are used to probe global patterns of activity, illuminating relative influences of test-set size and chemical versus biological space diversity on enrichment results. The results illustrate the power of CT-enrichment approaches to guide and inform future analysis of Tox21 chemical-activity datasets.

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