High-Throughput Screening to Predict Chemical-Assay Interference.

Scientific Reports
Alexandre BorrelNicole C Kleinstreuer

Abstract

The U.S. federal consortium on toxicology in the 21st century (Tox21) produces quantitative, high-throughput screening (HTS) data on thousands of chemicals across a wide range of assays covering critical biological targets and cellular pathways. Many of these assays, and those used in other in vitro screening programs, rely on luciferase and fluorescence-based readouts that can be susceptible to signal interference by certain chemical structures resulting in false positive outcomes. Included in the Tox21 portfolio are assays specifically designed to measure interference in the form of luciferase inhibition and autofluorescence via multiple wavelengths (red, blue, and green) and under various conditions (cell-free and cell-based, two cell types). Out of 8,305 chemicals tested in the Tox21 interference assays, percent actives ranged from 0.5% (red autofluorescence) to 9.9% (luciferase inhibition). Self-organizing maps and hierarchical clustering were used to relate chemical structural clusters to interference activity profiles. Multiple machine learning algorithms were applied to predict assay interference based on molecular descriptors and chemical properties. The best performing predictive models (accuracies of ~80%) have been ...Continue Reading

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Citations

May 19, 2020·Nucleic Acids Research·Alexandre BorrelNicole C Kleinstreuer
Feb 14, 2021·Drug Discovery Today·Zi-Yi YangDong-Sheng Cao
Dec 22, 2020·Chemical Research in Toxicology·Shagun KrishnaNicole Kleinstreuer
Mar 20, 2021·Expert Opinion on Drug Discovery·David Z HuangSogole Sami Bahmanyar
Jul 3, 2021·International Journal of Molecular Sciences·Maša KendaMarija Sollner Dolenc
Jul 18, 2020·Journal of Chemical Information and Modeling·Vinicius M AlvesAlexander Tropsha
Jun 25, 2021·Toxicological Sciences : an Official Journal of the Society of Toxicology·Anne MilcampsJenny Odum

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Methods Mentioned

BETA
Assay
PCA
structure-based prediction

Software Mentioned

SOM
bcutp
rpart
QSAR
DSSTOX
OPERA
pls
CombDipolPolariz
RDKit kit
PyDPI python library

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