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Applications of a Chemotype-Enrichment Approach to the ToxCast Data Landscape and Beyond: Inverting the SAR Paradigm
Citation:
Richard, A., R. Lougee, Chris Grulke, N. Baker, J. Wang, AND A. Williams. Applications of a Chemotype-Enrichment Approach to the ToxCast Data Landscape and Beyond: Inverting the SAR Paradigm. Presented at American Chemical Society Spring meeting, Orlando, FL, March 31 - April 04, 2019. https://doi.org/10.23645/epacomptox.8083343
Impact/Purpose:
Abstract and presentation for American Chemical Society spring meeting 2019
Description:
Traditional structure-activity relationship (SAR) approaches to modeling in toxicology are bounded and determined by the chemicals in the tested space, and are limited by such factors as size and structure diversity of that tested space, mechanistic diversity of the activity endpoint, and percentage of actives. A chemotype (CT)-enrichment approach inverts this paradigm and creates a static chemical abstraction layer consisting of structural features that define local chemistry domains upon which diverse test sets and biological outcomes (or binary categorical assignments of any sort) can be projected. A recently developed Chemotype-Enrichment Workflow (CTEW), based on a publicly available set of ToxPrint chemical features, has been applied to a broad range of datasets spanning EPA’s Computational Toxicology research programs. The results have facilitated a global view of ToxCast high-throughput screening results for over 1000 assays as projected by enrichments within ToxPrint chemistry domains. From the vantage point of defined chemistry, various patterns are revealed, including the degree to which CT-biological activity signals are present in datasets not amenable to global SAR analysis, areas of CT-assay promiscuity, and areas of CT inactivity and possibly related analytical QC fails. Interesting patterns in CT enrichments can also be observed upon “tuning” of the biological signal within time-series for a given assay, and upon tuning of the CTs from more to less specific representations. CTEW analyses of a sample of individual bioassay datasets will be shown to illustrate the power of the approach to probe chemical-bioactivity patterns. This abstract does not necessarily represent the views or policies of the U.S. Environmental Protection Agency.
URLs/Downloads:
DOI: Applications of a Chemotype-Enrichment Approach to the ToxCast Data Landscape and Beyond: Inverting the SAR Paradigm
RICHARD_ACS_SPRING2019_SLIDES_V2.PDF (PDF, NA pp, 6598.791 KB, about PDF)