Bioactivity Signatures of Drugs vs. Environmental Chemicals Revealed by Tox21 High-Throughput Screening Assays

Abstract

Humans are exposed to tens of thousands of chemicals over the course of a lifetime, yet there remains inadequate data on the potential harmful effects of these substances on human health. Using quantitative high-throughput screening (qHTS), we can test these compounds for potential toxicity in a more efficient and cost-effective way compared to traditional animal studies. Tox21 has developed a library of ∼10,000 chemicals (Tox21 10K) comprising one-third approved and investigational drugs and two-thirds environmental chemicals. In this study, the Tox21 10K was screened in a qHTS format against a panel of 70 cell-based assays with 213 readouts covering a broad range of biological pathways. Activity profiles were compared with chemical structure to assess their ability to differentiate drugs from environmental chemicals, and structure was found to be a better predictor of which chemicals are likely to be drugs. Drugs and environmental chemicals were further analyzed for diversity in structure and biological response space and showed distinguishable, but not distinct, responses in the Tox21 assays. Inclusion of other targets and pathways to further diversify the biological response space covered by these assays is likely required to better evaluate the safety profile of drugs and environmental chemicals to prioritize for in-depth toxicological studies.

The Tox21 10K Compound Library: Collaborative Chemistry Advancing Toxicology

“…Interestingly, the peak of the EPA + NTP library distribution was biased toward greater oral rat LD 50 values (indicating overall lower potency) than the NCATS/NCATS drug library. This is likely due to the designed bioactivity and higher overall potencies of drugs relative to commercial and industrial chemicals, consistent with the results of Ngan et al 24 The remaining three plots in Figure 12 illustrate a substantial shift in the mean toward lower MolWt chemicals, with a related shift toward more volatile, higher vapor pressure chemicals in the EPA + NTP library versus the NCATS drug library. A corresponding shift toward greater complexity is seen for the NCATS library, consistent with the report of greater chemical diversity (less interlibrary molecular similarity) within the NCATS drug library 24 and is likely also associated with higher mean MolWt for this library, as shown in Figure 12.…”

“…This is likely due to the designed bioactivity and higher overall potencies of drugs relative to commercial and industrial chemicals, consistent with the results of Ngan et al 24 The remaining three plots in Figure 12 illustrate a substantial shift in the mean toward lower MolWt chemicals, with a related shift toward more volatile, higher vapor pressure chemicals in the EPA + NTP library versus the NCATS drug library. A corresponding shift toward greater complexity is seen for the NCATS library, consistent with the report of greater chemical diversity (less interlibrary molecular similarity) within the NCATS drug library 24 and is likely also associated with higher mean MolWt for this library, as shown in Figure 12. A ToxPrint heat map projection of each of the Tox21 partner libraries is presented in Figure 13 along with the total number of unique ToxPrints (present in three or more chemicals) represented in each of the three partner libraries as well as in the combined EPA + NTP library and in the full Tox21 library.…”

“…Note that a similar library split was made in a recent publication by Ngan et al in order to examine differential Tox21 assay activity in the ENVR (EPA + NTP minus NCATS library overlap) versus DRUG (NCATS library) chemical landscapes. 24 The authors reported that Tox21 assay activity profiles were less able to discriminate between the ENVR and DRUG libraries than was chemical structure. The authors also found that DRUGs had slightly higher overall activity hit rates.…”

Prediction Models for Agonists and Antagonists of Molecular Initiation Events for Toxicity Pathways Using an Improved Deep-Learning-Based Quantitative Structure–Activity Relationship System

“…The interaction between endocrine-disrupting chemicals and nuclear–receptor family proteins can affect the endocrine system in the AOP [ 4 ]. The Toxicology in the 21st Century (Tox21) program is a US federal research collaboration between the US Environmental Protection Agency, the National Toxicology Program, the National Center for Advancing Translational Sciences, and the Food and Drug Administration that aims to develop toxicity assessment methods for commercial chemicals, pesticides, food additives/contaminants, and medical products using quantitative high-throughput screening [ 5 , 6 , 7 ]. The Tox21 10K library consists of approximately 10,000 (10K) chemicals, including nearly 100 million data points obtained by in vitro quantitative high-throughput screening, indicating the toxicological risk of chemical compounds obtained using an in silico approach [ 8 , 9 ].…”

Repurposing drugs as COVID-19 therapies: A toxicity evaluation

“… 9 Several toxicity-related assays were found to be significantly correlated with the CPE assay, including a hERG assay ( r = 0.36, P <1×10 –20 ), [12] , [13] a PLD assay ( r = 0.34, P = 1.02×10 –14 ), [12] , [13] , [14] , [15] and 39 cell viability assays ( P <0.01; Table S1 in the supplemental information online). [16] , [17] , [18] , [19] Drug-induced blockage of the hERG channel can lead to QT interval prolongation and torsades de pointes (TdP), a potentially lethal ventricular tachyarrhythmia, and these adversities have been obstacles in drug development. 20 Therefore, it is crucial to highlight the hERG liability of compounds early on during the preclinical phase of drug discovery.…”