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

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.

Papaverinol-N-Oxide: A Microbial Biotransformation Product of Papaverine with Potential Antidiabetic and Antiobesity Activity Unveiled with In Silico Screening

“…It is likely that blocking the potassium channels that hERG encodes would result in dangerous ventricular arrhythmia. All examined compounds can suppress hERG II but not hERG I, according to numerous studies [ 37 ]. However, it was anticipated that papaverine and metabolites 3 – 5 would be hepatotoxic and cause liver damage as a result of the drugs.…”

Activity Prediction of Various Herbicides against Honey Bee, Avian, and Multiple Human Leukemia, CNS, Ovarian, Prostate Cancer Cell Lines

“…Chemical(s) in early drug development phase or candidate drug related to cardio-toxicity issue can be predicated via inhibition of affinity to hERG by animal, ex vivo, or in Silico studies. In Silico method is a favorite method because it is low costly, high throughput, computerized output, with absence of experimental lab requirements providing faster cardio-toxicity estimation [53]. Here, online estimation machine model by http://biosig.unimelb.edu.au/pkcsm/ website specified unexpected results where all 30 herbicides under testing showed NO hERG I inhibition while only P1 had hERG II inhibition (Tables 2 & 3) and (Figure 8).…”

Repurposing drugs as COVID-19 therapies: A toxicity evaluation

“…Imatinib has shown in vitro antiviral activity against SARS-CoV-1 and Middle East respiratory syndrome (MERS)-CoV, which is related to SARS-CoV-2; thus, it has been postulated that this drug could be an unexplored treatment for SARS-CoV-2 infection. [55] , [56] Several clinical trials (e.g., NCT04394416, Phase III) are underway to evaluate the safety and efficacy of imatinib for the treatment of SARS-CoV-2. Similarly, chlorpromazine (high hERG liability, cluster 99) has been shown to inhibit in vitro viral replication of SARS-CoV-1 and MERS-CoV.…”