Site of Reactivity Models Predict Molecular Reactivity of Diverse Chemicals with Glutathione

Drug
toxicity is often caused by electrophilic reactive metabolites
that covalently bind to proteins. Consequently, the quantitative strength
of a molecule’s reactivity with glutathione (GSH) is a frequently
used indicator of its toxicity. Through cysteine, GSH (and proteins)
scavenges reactive molecules to form conjugates in the body. GSH conjugates
to specific atoms in reactive molecules: their sites of reactivity.
The value of knowing a molecule’s sites of reactivity is unexplored
in the literature. This study tests the value of site of reactivity
data that identifies the atoms within 1213 reactive molecules that
conjugate to GSH and builds models to predict molecular reactivity
with glutathione. An algorithm originally written to model sites of
cytochrome P450 metabolism (called XenoSite) finds clear patterns
in molecular structure that identify sites of reactivity within reactive
molecules with 90.8% accuracy and separate reactive and unreactive
molecules with 80.6% accuracy. Furthermore, the model output strongly
correlates with quantitative GSH reactivity data in chemically diverse,
external data sets. Site of reactivity data is nearly unstudied in
the literature prior to our efforts, yet it contains a strong signal
for reactivity that can be utilized to more accurately predict molecule
reactivity and, eventually, toxicity.