DockTox: Targeting molecular initiating events in organ toxicity through molecular docking

Adverse Outcome Pathways (AOPs) in toxicology describe the sequence of key events from chemical exposure to adverse outcomes, facilitating the development of predictive models. The EU ONTOX project uses this framework to predict liver, developmental brain, and kidney toxicity without animal testing. Focusing on Molecular Initiating Events (MIEs), more concretely on the interaction of chemicals with key proteins, we have developed an automated workflow for docking small molecules onto over 20 pre-processed protein structures, implemented in the online tool DockTox. This tool generates conformers of small molecules, performs docking on MIE-associated proteins, and provides binding energy, interacting residues, and interaction maps. Additionally, it compares the interactions to a reference list of known ligands, producing an interaction fraction as an additional similarity measure. Evaluation of the docking workflow’s predictive performance on Peroxisome Proliferator-Activated Receptor α (PPARα) showed that interaction fraction values are more informative than binding energy alone for distinguishing binders from non-binders. This unique feature enhances the understanding of target protein interactions. DockTox supports the virtual screening of small molecules targeting MIE-associated proteins, offering insights into binding energies and interaction profiles. It is a valuable tool for anticipating adverse outcomes from chemical exposure in a tiered risk assessment approach.