Screening of 6000 compounds for uncoupling activity: input parameters, the predicted uncoupling activity, as well as the results in respect to structural alerts

Protonophoric uncoupling of phosphorylation is an important factor when
assessing chemicals for their toxicity, and has recently moved into focus
in pharmaceutical research with respect to the treatment of diseases such
as cancer, diabetes or obesity. Reliably identifying uncoupling
activity is thus a valuable goal. To that end, we screened more than 6000
anionic compounds for in-vitro uncoupling activity, using a biophysical
model based on ab-initio COSMO-RS input parameters with the molecular
structure as the only external input. We combined these results with a
model for baseline toxicity (narcosis). Our model identified more than
1250 possible uncouplers in the screening dataset, and identified possible
new uncoupler classes such as thiophosphoric acids. When tested against
423 known uncouplers and 612 known inactive compounds in the dataset, the
model reached a sensitivity of 83% and a specificity of 96%. In a direct
comparison, it showed a similar specificity than the structural alert
profiler Mitotox (97%), but much higher sensitivity than Mitotox (47%).
The biophysical model thus allows for a more accurate screening for
uncoupling activity than existing structural alert profilers. We propose
to use our model as a complementary tool to screen large datasets for
protonophoric uncoupling activity in drug development and toxicity
assessment.