Machine Learning Tool for New Selective Serotonin and Serotonin–Norepinephrine Reuptake Inhibitors

Depression, a serious mood disorder, affects about 5% of the population. Currently, there are two groups of antidepressants that are the first-line treatment for depressive disorder: selective serotonin reuptake inhibitors and serotonin–norepinephrine reuptake inhibitors. The aim of the study was to develop Quantitative Structure–Activity Relationship (QSAR) models for serotonin (SERT) and norepinephrine (NET) transporters to predict the affinity and inhibition potential of new molecules. Models were developed using the Automated Machine Learning tool Mljar based on 80% of the dataset according to 10-fold cross-validation and externally validated on the remaining 20% of data. The molecular representation featured two-dimensional Mordred descriptors. For each model, Shapley additive explanations analysis was performed to clarify the influence of the descriptors on the models’ predictions. Based on the final QSAR models, the following results were obtained: NET and pIC50 value RMSE_test = 0.678, R²_test = 0.640; NET and pKi RMSE_test = 0.590, R²_test = 0.709; SERT and pIC50 RMSE_test = 0.645, R²_test = 0.678; SERT and pKi value RMSE_test = 0.540, R²_test = 0.828. QSAR models for serotonin and norepinephrine transporters have been made available in a new module of the SerotoninAI application to enhance usability for scientists.