Predictive Modeling of Estrogen Receptor Agonism, Antagonism, and Binding Activities Using Machine and Deep Learning Approaches

As defined by the World Health Organization, an endocrine disruptor is an exogenous substance or mixture that alters function(s) of the endocrine system and consequently causes adverse health effects in an intact organism, its progeny, or (sub)populations. Traditional experimental testing regimens to identify toxicants that induce endocrine disruption can be expensive and time-consuming. Computational modeling has emerged as a promising and cost-effective alternative method for screening and prioritizing potentially endocrine active compounds. The efficient identification of suitable chemical descriptors and machine learning algorithms, including deep learning, is a considerable challenge for computational toxicology studies. Here, we sought to apply classic machine learning algorithms and deep learning approaches to a panel of over 7,500 compounds tested against 18 Toxicity Forecaster (ToxCast) assays related to nuclear estrogen receptor (ERα and ERβ) activity. Three binary fingerprints (Extended Connectivity FingerPrints, Functional Connectivity FingerPrints, and Molecular ACCess System) were used as chemical descriptors in this study. Each descriptor was combined with four machine learning, and two deep learning (normal and multitask neural networks) approaches to construct models for all 18 ER assays. The resulting model performance was evaluated using the area under the receiving operating curve (AUC) values obtained from a five-fold cross-validation procedure. The results showed that individual models have AUC values that range from 0.56 to 0.86. External validation was conducted using two additional sets of compounds (n=592 and n=966) with established interactions with nuclear ER demonstrated through experimentation. An agonist, antagonist, or binding score was determined for each compound by averaging its predicted probabilities in relevant assay models as an external validation, yielding AUC values ranging from 0.63 to 0.91. The results suggest that multitask neural networks offer advantages when modeling mechanistically-related endpoints. Consensus predictions based on the average values of individual models remain the best modeling strategy for computational toxicity evaluations.