Binding Affinity Ranking at the Molecular Initiating Event (BARMIE): An open-source computational pipeline for ecological hazard ranking of endocrine disrupting chemicals.

A challenge in ecological risk assessment is identifying the chemicals that pose the greatest threat and determining which species are most vulnerable to them. To help address this, the study has developed an open-source tool called BARMIE (Binding Affinity Ranking at the Molecular Initiating Event) to rapidly predict the chemical binding affinity of steroid receptor proteins to synthetic steroids, and, when combined with an in vitro transactivation assay, to identify novel endocrine-disrupting chemicals (EDCs). BARMIE was used to screen 163 teleost fish glucocorticoid receptors (GRs) for binding to the natural ligand cortisol and to 10 synthetic glucocorticoid drugs (GCs) designed to interact within the ligand-binding pocket (LBP) of GRs. GC halcinonide was predicted to have the most significant binding affinity, and species from the superorder Protacanthopterygii were identified as having high-affinity GRs. BARMIE was then used to screen the binding profiles to compounds of the Medicine for Malaria Venture Global Health Priority Box to rainbow trout GRs (rtGR1 and rtGR2). Of the 178 compounds, 24 and 36 bound within the LBP with an affinity [≥] -7.5 kcal/mol to the rtGR1 and rtGR2, respectively. For 30 of these compounds, transactivation activity was assessed at 1{micro}M in the presence or absence of 1{micro}M cortisol. Compound #18, a 1,2,4-oxadiazole, a compound known to have biological activities, significantly stimulated both rtGR1 and rtGR2, as well as enhanced the activity in the presence of cortisol, and compound #14, a predicted IL-1R-associated kinase four inhibitor (IRAK4) inhibitor, had antagonist properties in both receptors. Neither has been shown to affect fish GR functioning previously.