Ensemble machine learning to evaluate the in vivo acute oral toxicity and in vitro human acetylcholinesterase inhibitory activity of organophosphates

Organophosphates (OPs) are hazardous chemicals widely used in industry and agriculture. Distribution of their residues in nature causes serious risks to humans, animals, and plants. To reduce hazards from OPs, quantitative structure–activity relationship (QSAR) models for predicting their acute oral toxicity in rats and mice and inhibition constants concerning human acetylcholinesterase were developed according to the bioactivity data of 456 unique OPs. Based on robust, two-dimensional molecular descriptors and quantum chemical descriptors, which accurately reflect OP electronic structures and reactivities, the influences of eight machine-learning algorithms on the prediction performance of the QSAR models were explored, and consensus QSAR models were constructed. Several strict model validation indices and the results of applicability domain evaluations show that the established consensus QSAR models exhibit good robustness, practical prediction abilities, and wide application scopes. Poor correlation was observed between acute oral toxicity at the mammalian level and the inhibition constants at the molecular level, indicating that the acute toxicity of OPs cannot be evaluated only by the experimental data of enzyme inhibitory activity, their toxicokinetic characteristics must also be considered. The constructed QSAR models described herein provide rapid, theoretical assessment of the bioactivity of unstudied or unknown OPs, as well as guidance for making decisions regarding their regulation.