Molecular Insights into the Binding of Organophosphate Flame Retardant Key Metabolites with Mineralocorticoid and Estrogen Receptors

Flame retardants (FR) encompass a wide range of chemicals designed to inhibit and reduce the spread of fire by forming protective layers on materials. While originally considered relatively safe due to their rapid metabolism, growing evidence indicates that organophosphate flame retardants (OPFRs) can be extensively released into the environment, leading to toxic effects in humans, particularly endocrine disruption. Although the endocrine-disrupting potential of OPFRs is well-documented, the mechanisms through which their metabolites exert toxic effects remain largely unexplored. In this study, a comprehensive computational framework incorporating molecular docking, density functional theory, and all-atom molecular dynamic simulations were employed to investigate the binding and interactions of three key OPFR metabolites, BCIPP, BDCIPP, and DPHP, with human estrogen receptors (ER) and mineralocorticoid receptors (MR). The results revealed that these metabolites formed stable and compact complexes with both MR and ER, although high per residue atomic fluctuations were observed in ER complexes, likely due to the reactive nature of the metabolites. Binding free energy analysis further indicated favorable interactions between the OPFR metabolites and target receptors. Principal component analysis, leveraging machine learning algorithms, showed consistent motion, while free energy profiles demonstrated stable energy basins with minimal variations. These findings suggest that OPFR metabolites have strong binding affinities with MR and ER, hinting at their potential endocrine-disrupting effects at the molecular level. This study lays the groundwork for future research into the hazards posed by OPFR metabolites.