Toxicology in the 21st Century Program (Tox21) - Computational Toxicology

National Center For Advancing Translational Sciences

Investigators

Linked publications, trials & patents

Abstract

The Tox21 Programs federal partners include the Environmental Protection Agency (EPA), the Food and Drug Administration (FDA) and NIH, with leadership from NCATS and the National Toxicology Program (NTP) at the National Institute of Environmental Health Sciences (NIEHS). These agencies work together to advance in vitro toxicological testing. The Tox21 Program can be separated into three NCATS teams: Systems Toxicology, Genomic Toxicology, and Computational Toxicology. The Tox21 Computational Toxicology team has enhanced a variety of tools that are routinely used by Tox21 partners to access each others data. The team performed data analysis of six assays that were identified, developed, optimized, and/or screened by the Tox21 systems toxicology team and gene expression and high throughput neurotoxicity assay data generated by the Tox21 Genomic Toxicology team. These activities include normalization and correction, fitting of concentration-response curves to generate potency and efficacy measures, classification of curves based on a set of criteria that included significance of fit (measured by p-values), completeness of fit, and efficacy, evaluation of assay performance by data reproducibility, data driven selection of compounds for follow up studies, and identification of genes and pathways involved in cell responses to chemical exposure. In addition, the Tox21 Computational Toxicology team has updated the web-based, automated structure-activity relationship (SAR) analysis tool for the systems toxicology team to conduct SAR analysis on all 10K library screens. The Tox21 Computational Toxicology team has also updated the Tox21 Assay Tracking System that stores the assay annotations and detailed experimental conditions and screening protocols for all the Tox21 assays. The 10K data from all assays screened up to FY21 have been made public in PubChem totaling 229 assay entries (AIDs) and nearly 102 million data points. The Tox21 public data browser has been updated with the latest assay results from the 10K library screens totaling 78 assays. This browser provides the public with visualization of Tox21 qHTS data including concentration-response curves, curve fitting results and different activity metrics along with chemical structure and analytical QC results. Data are searchable by assay and/or chemical. Results from multiple assays and/or chemicals can be overlaid for ease of comparison. All data as well as assay descriptions and detailed screening protocols (SLPs) are available for download. The Tox21 Computational Toxicology team has continued to work with the Tox21 chemical working group to update the Tox21 10K library chemical QC results, including the 4-month compound stability test results. All QC results have been released in the public Tox21 Browser (https://tripod.nih.gov/tox/samples) and the Browser was updated with links to the EPA CompTox Chemicals Dashboard. In FY22, the Tox21 Computational Toxicology team has been working with other NCATS teams to update the NCATS Pharmaceutical Collection (NPC), which is part of the Tox21 10K compound library, with drugs approved in recent years to include an up-to-date list of all approved drugs. In addition, the teams have been working on constructing a collection of clinically tested compounds to complement the NPC in FY22. The Tox21 Computational Toxicology team is also leading one of the Tox21 cross-partner projects Expansion of Pathway Coverage by Tox21 High-Throughput Screening Assays for Better Prediction of Adverse Drug Effects, which utilizes the NCATS BioPlanet (https://tripod.nih.gov/bioplanet/) as a tool to define the biological space and identify assays for screening. The data generated from this project will be used to build computational models to predict liver and cardiotoxicity. In addition, the Tox21 Computational Toxicology team has continued to work with the Tox21 Genomic Toxicology team to refine methods for concentration response gene expression data analysis including strategies for point-of-departure (PoD) determination. A web version of the software platform for visualization and analysis of concentration response gene expression data has been developed and will be made public in due course. In FY22, the Tox21 Computational Toxicology team has been collaborating with the Analytical Chemistry Core of DPI on the analysis of high throughput proteomics data resulting in one publication in Analytical Chemistry in FY22. The Tox21 Computational Toxicology team collaborated with the TDB chemistry team on the development of a high-throughput platform for novel reaction discovery, for which the Computational Toxicology team applied statistical methods to evaluate high-throughput chemical reaction data. This collaboration resulted in a publication in the European Journal of Chemistry in FY22. The Tox21 Computational Toxicology team continued to collaborate with the TDB biology team in FY22 to develop computational models for the identification of novel anti-SARS-CoV-2 compounds that target either the virus cell entry or the viral 3CL protease. Moreover, the Tox21 Computational Toxicology team collaborated with the Tox21 Systems Toxicology team and the TDB biology team to evaluate the potential toxicity liabilities of anti-SARS-CoV-2 compounds as drug repurposing candidates. These collaborative efforts have resulted in two papers published in Drug Discovery Today and Journal of Medicinal Chemistry, respectively, in FY22.