Systematic evaluation of Tox21 compounds that target β-adrenergic receptors and their role in cardiotoxicity

Abstract

β-adrenergic receptors play important roles in heart failure and drug-induced cardiotoxicity (DICT). The Tox21 10 K library of drugs and environmental chemicals have been tested for their activity against β-adrenergic receptor subtypes 1 and 2 (ADRB1 and ADRB2), as well as inhibition of the human ether-à-go-go-related gene (hERG) in a quantitative high-throughput screening (qHTS) format. In this study, the Tox21 compound activity profiles in the ADRB1/2 and hERG assays were compared in relation to their DICT potential. The results showed that compounds that acted as ADRB1 agonists, ADRB2 antagonists, or hERG inhibitors were more likely to exhibit DICT. The ADRB1 and ADRB2 assays shared similar compound activity profiles, while the hERG inhibition assay identified a distinct set of active compounds. In addition, we identified structural features that may differentiate the cardiotoxic and non-toxic ADRB1 agonists. Finally, machine learning models were developed for ADRB1 activity prediction based on chemical structure. The models were used to virtually screen a collection of approximately 360 K diverse compounds, with the highest-ranked compounds selected for experimental validation. This work represents the first systematic study of drugs and environmental chemicals against ADRB1/2, providing important insights into β-adrenergic receptor-related cardiotoxicity mechanisms. By clarifying how specific pharmacological interactions contribute to cardiac risk, it provides a framework for early cardiotoxicity prediction and the design of safer therapeutics through integrated profiling and modeling.