Cheminformatics Analysis of the Multitarget Structure–Activity Landscape of Environmental Chemicals Binding to Human Endocrine Receptors

In human exposome, environmental chemicals can target
and disrupt
different endocrine axes, ultimately leading to several endocrine
disorders. Such chemicals, termed endocrine disrupting chemicals,
can promiscuously bind to different endocrine receptors and lead to
varying biological end points. Thus, understanding the complexity
of molecule–receptor binding of environmental chemicals can
aid in the development of robust toxicity predictors. Toward this,
the ToxCast project has generated the largest resource on the chemical–receptor
activity data for environmental chemicals that were screened across
various endocrine receptors. However, the heterogeneity in the multitarget
structure–activity landscape of such chemicals is not yet explored.
In this study, we systematically curated the chemicals targeting eight
human endocrine receptors, their activity values, and biological end
points from the ToxCast chemical library. We employed dual-activity
difference and triple-activity difference maps to identify single-,
dual-, and triple-target cliffs across different target combinations.
We annotated the identified activity cliffs through the matched molecular
pair (MMP)-based approach and observed that a small fraction of activity
cliffs form MMPs. Further, we structurally classified the activity
cliffs and observed that R-group cliffs form the highest fraction
among the cliffs identified in various target combinations. Finally,
we leveraged the mechanism of action (MOA) annotations to analyze
structure–mechanism relationships and identified strong MOA-cliffs
and weak MOA-cliffs, for each of the eight endocrine receptors. Overall,
insights from this first study analyzing the structure–activity
landscape of environmental chemicals targeting multiple human endocrine
receptors will likely contribute toward the development of better
toxicity prediction models for characterizing the human chemical exposome.