Endocrine-disrupting activity of per- and polyfluoroalkyl substances: Exploring combined approaches of ligand and structure based modeling

Exposure to perfluorinated and polyfluoroalkyl substances (PFCs/PFASs), endocrine disrupting halogenated pollutants, has been linked to various diseases including thyroid toxicity in human populations across the globe. PFASs can compete with thyroxine (T4) for binding to the human thyroid hormone transport protein transthyretin (TTR) which may lead to reduce thyroid hormone levels leading to endocrine disrupting adverse effects. Environmental fate and endocrine-disrupting activity of PFASs has initiated several research projects, but the amount of experimental data available for these pollutants is limited. In this study, experimental data for T4-TTR competing potency of 24 PFASs obtained in a radioligand-binding assay were modeled using classification- and regression-based quantitative structure-activity relationship (QSAR) tools with simple molecular descriptors obtained from chemical structure of these compounds in order to identify the responsible structural features and fragments of the studied PFASs for endocrine disruption activity. Additionally, docking studies were performed employing the crystal structure complex of TTR with bound 2′, 6′-difluorobiphenyl-4-carboxylic acid (PDB: 2F7I) in order to constitute the receptor model for human TTR. The results corroborate evidence for these binding interactions and indicate multiple high-affinity modes of binding. The developed in silico models therefore advance our understanding of important structural attributes of these chemicals and may provide important information for the design of future synthesis of PFASs as well as may serve as an efficient query tool for virtual screening of large PFAS databases to check their endocrine toxicity profile.