Control list of high-priority chemicals based on 5-HT-RI functionality and the human health interference effects...

The antidepressant drug known as 5-HT reuptake inhibitor (5-HT-RI) was commonly detected in biological tissues and result in significant adverse health effects. Homology modeling was used to characterize the functionalities (efficacy and resistance), and the adverse outcome pathway was used to characterize its human health interferences (olfactory toxicity, neurotoxicity, and gut microbial interference). The convolutional neural network coupled with the gated recurrent unit (CNN-GRU) deep learning method was used to construct a comprehensive model of 5-HT-RI functionality and human health interference effects selectivity with small sample data. The architecture with 2 SE, 320 neuronal nodes and 6-folds cross-validation showed the best applicability. The results showed that the confidence interval of the constructed model reached 90 % indicating that the model had reliable prediction ability and generalization ability. Based on the CNN-GRU deep learning model, seven high-priority chemicals with a weak comprehensive effect, including D-VEN, (1R,4S)-SER, S-FLX, CTP, S-CTP, NEF, and VEN, were screened. Based on the molecular three-dimensional structure information, a comprehensive-effect three-dimensional quantitative structure-activity relationship (3D-QSAR) model was constructed to confirm the reliability of the constructed control list of 5-HT-RI high-priority chemicals. Analysis with the ranking of calculated values based on the molecular dynamics method and predicted values based on the CNN-GRU deep learning model, we found that the consistency of the three methods was above 85 %. Additionally, by analyzing the sensitivity, molecular electrostatic potential, polar surface area of the comprehensive-effect CNN-GRU deep learning model, and the electrostatic field of the 3D-QSAR models, we found that the significant effects of five key characteristics (DM, Q_yy, Q_xz, I, and BP), molecular electronegativity, and polarity significantly affected the high-priority degree of 5-HT-RI. In this study, we provided reasonable and reliable prediction tools and discussed theoretical methods for the risk assessment of functionality and human health interference of emerging pollutants such as 5-HT-RI.