Predicting Uncoupling Toxicity of Organic Acids Based on Their Molecular Structure Using a Biophysical Model

Area of Science:

• Computational chemistry
• Toxicology
• Biophysics

Background:

• Organic acids can uncouple cellular energy production.
• Predicting this protonophoric uncoupling activity (ECw) is crucial for chemical safety.
• Existing methods often require extensive experimental data.

Purpose of the Study:

• To develop a purely mechanistic model for predicting protonophoric uncoupling activity (ECw) of organic acids.
• To enable toxicity predictions using only chemical structure information.
• To provide insights into factors influencing uncoupling activity.

Main Methods:

• Developed a mechanistic model incorporating monomer and heterodimer permeation.
• Input parameters derived solely from the chemical structure of organic acids.
• Validated the model against literature data from various biological systems (chromatophores, mitochondria, algae).

Main Results:

• The model successfully predicted ECw values across different experimental systems.
• Accurate reproduction of pH-dependencies in isolated mitochondria and intact cells.
• Demonstrated the model's ability to predict ECw based on chemical structure alone.

Conclusions:

• The mechanistic model offers a valuable tool for early-stage toxicity assessment of organic chemicals.
• The model provides mechanistic insights into protonophoric uncoupling, aiding drug design and chemical regulation.
• Structure-based prediction of ECw facilitates efficient chemical development and safety evaluation.