High-Throughput Chemical Screening and Structure-Based Models to Predict hERG Inhibition

SIMPLE SUMMARY: Cardiovascular disease is the leading cause of death for people of most ethnicities in the United States. The human ether-a-go-go-related gene (hERG) potassium channel plays a pivotal role in cardiac rhythm regulation, and cardiotoxicity associated with hERG inhibition by drug molecules and environmental chemicals is a major public health concern. An evaluation of the effect of environmental chemicals on hERG channel function can help inform the potential public health risks of these compounds. To assess the cardiotoxic effect of diverse drugs and environmental compounds, the Tox21 federal research program has screened a collection of 9667 chemicals for inhibitory activity against the hERG channel. A set of molecular descriptors covering physicochemical and structural properties of chemicals, self-organizing maps, and hierarchical clustering were applied to characterize the chemicals inhibiting hERG. Machine learning approaches were applied to build robust statistical models that can predict the probability of any new chemical to cause cardiotoxicity via this mechanism. ABSTRACT: Chemical inhibition of the human ether-a -go-go-related gene (hERG) potassium channel leads to a prolonged QT interval that can contribute to severe cardiotoxicity. The adverse effects of hERG inhibition are one of the principal causes of drug attrition in clinical and pre-clinical development. Preliminary studies have demonstrated that a wide range of environmental chemicals and toxicants may also inhibit the hERG channel and contribute to the pathophysiology of cardiovascular (CV) diseases. As part of the US federal Tox21 program, the National Center for Advancing Translational Science (NCATS) applied a quantitative high throughput screening (qHTS) approach to screen the Tox21 library of 10,000 compounds (~7871 unique chemicals) at 14 concentrations in triplicate to identify chemicals perturbing hERG activity in the U2OS cell line thallium flux assay platform. The qHTS cell-based thallium influx assay provided a robust and reliable dataset to evaluate the ability of thousands of drugs and environmental chemicals to inhibit hERG channel protein, and the use of chemical structure-based clustering and chemotype enrichment analysis facilitated the identification of molecular features that are likely responsible for the observed hERG activity. We employed several machine-learning approaches to develop QSAR prediction models for the assessment of hERG liabilities for drug-like and environmental chemicals. The training set was compiled by integrating hERG bioactivity data from the ChEMBL database with the Tox21 qHTS thallium flux assay data. The best results were obtained with the random forest method (~92.6% balanced accuracy). The data and scripts used to generate hERG prediction models are provided in an open-access format as key in vitro and in silico tools that can be applied in a translational toxicology pipeline for drug development and environmental chemical screening.