Structure–Activity Relationship of Protein-Mediated Molecular Initiating Events of Organ-Specific Toxicities

Toxicological research
is facing a major transition from
animal
models into in vitro and in silico models to improve the cost-effectiveness of the testing process,
shorten the timeline for primary screening of chemicals, and better
align with the 3Rs principles to reduce animal suffering. In this
work, structure–activity relationships were developed based
on structural alerts (SAs) that flag the ability of chemicals to trigger
specific molecular initiating events (MIEs) upstream of five adversities
(cholestasis, steatosis, kidney tubular necrosis, cognitive functional
defects, and neural tube closure defects). Twenty-nine protein targets
linked to MIEs were identified from published adverse outcome pathway
networks, while bioactivity data for chemicals against such targets
were collected from ChEMBL 35 database. SARpy 2.0 included in the
novel ΔQSAR (DeltaQSAR) software was used to extract rulesets,
i.e., collections of structural alerts codifying for protein bioactivity.
The rulesets were evaluated using an external test set to assess their
real-life predictivity. Good external validation performance was achieved
for 22 out of 29 rulesets that returned balanced accuracy ≥
70% and coverage ≥ 70%, confirming that these rulesets can
be used for high-throughput as well as preliminary testing of chemicals.
Moreover, combining structure–activity relationship with the
adverse outcome pathway concept provides a mechanistic basis to the
prediction suggested by the rulesets.