Predictive Structure-Based Toxicology Approaches to Assess the Androgenic Potential of Chemicals

We present a practical and easy-to-run in silico workflow exploiting a structure-based strategy making use of docking simulations to derive highly predictive classification models of the androgenic potential of chemicals. Models were trained on a high-quality chemical collection comprising 1689 curated compounds made available within the CoMPARA consortium from the US Environmental Protection Agency and were integrated with a two-step applicability domain whose implementation had the effect of improving both the confidence in prediction and statistics by reducing the number of false negatives. Among the nine androgen receptor X-ray solved structures, the crystal 2PNU (entry code from the Protein Data Bank) was associated with the best performing structure-based classification model. Three validation sets comprising each 2590 compounds extracted by the DUD-E collection were used to challenge model performance and the effectiveness of Applicability Domain implementation. Next, the 2PNU model was applied to screen and prioritize two collections of chemicals. The first is a small pool of 12 representative androgenic compounds that were accurately classified based on outstanding rationale at the molecular level. The second is a large external blind set of 55450 chemicals with potential for human exposure. We show how the use of molecular docking provides highly interpretable models and can represent a real-life option as an alternative nontesting method for predictive toxicology.