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

Area of Science:

• Toxicology
• Computational Chemistry
• Drug Discovery

Background:

• Adverse Outcome Pathways (AOPs) provide a framework for predicting chemical toxicity.
• The EU ONTOX project aims to reduce animal testing for toxicity predictions.
• Molecular Initiating Events (MIEs) are crucial for understanding chemical interactions with proteins.

Purpose of the Study:

• To develop an automated workflow for docking small molecules to MIE-associated proteins.
• To create an online tool, DockTox, for predicting chemical toxicity.
• To evaluate the predictive performance of docking metrics.

Main Methods:

• Developed an automated docking workflow for over 20 pre-processed protein structures.
• Implemented the workflow in the online tool DockTox.
• Generated small molecule conformers, performed docking, and analyzed binding energy, residues, and interaction maps.
• Introduced an interaction fraction for comparing chemical interactions to known ligands.

Main Results:

• DockTox successfully docks small molecules to MIE-associated proteins.
• Interaction fraction proved more informative than binding energy for distinguishing binders from non-binders, using PPARα as a model.
• The tool provides insights into binding energies and interaction profiles.

Conclusions:

• DockTox enhances the understanding of target protein interactions in toxicology.
• The tool supports virtual screening for anticipating adverse outcomes from chemical exposure.
• DockTox is a valuable asset for tiered risk assessment strategies, reducing reliance on animal testing.