Developmental neurotoxicity (DNT) QSAR combination prediction model establishment and structural characteristics interpretation

With the incidence of neurodevelopmental disorders on the rise, it is imperative to screen and evaluate developmental neurotoxicity (DNT) compounds from a large number of environmental chemicals and understand their mechanisms. In this study, DNT qualitative structure-activity relationship (QSAR) study was carried out for the first time based on DNT data of mammals and structural characterization of DNT compounds was preliminarily illustrated. Five different classification algorithms and two feature selection methods were used to construct prediction models. The best model had good predictive ability on the external test set, but a small application domain (AD). Through combining of three different models, both MCC and AD values were improved. Furthermore, electronical properties, van der Waals volume-related properties and S, Cl or P containing substructure were found to be associated with DNT through modeling descriptors analysis and structure alerts (SAs) identification. This study lays a foundation for further DNT prediction of environmental exposures in human and contributes to the understanding of DNT mechanism. Graphical Abstract

Automated summary

With the increasing incidence of neurodevelopmental disorders, it is important to screen and evaluate developmental neurotoxicity (DNT) compounds from a large number of environmental chemicals and understand their mechanisms. This study conducted a DNT qualitative structure-activity relationship (QSAR) study for the first time, and preliminarily illustrated the structural characterization of DNT compounds. Multiple models and methods were used to construct prediction models, resulting in the best model with good predictive ability. By combining different models, both MCC values and application domain values were improved. Additionally, through modeling descriptors analysis and structure alerts (SAs) identification, electronical properties, van der Waals volume-related properties, and S, Cl or P containing substructure were found to be associated with DNT. This study lays a foundation for further DNT prediction of environmental exposures in human and contributes to the understanding of DNT mechanism.