Avoidance of the Ames test liability for aryl-amines via computation

Area of Science:

• Computational chemistry
• Medicinal chemistry
• Toxicology

Background:

• Aryl-amines are crucial in drug discovery but can be mutagenic.
• Mutagenicity stems from metabolic activation to reactive nitrenium cations that damage DNA.

Purpose of the Study:

• To assess the reliability of in silico calculations for predicting aryl-amine mutagenicity.
• To correlate theoretical nitrenium ion formation energies with Ames test results.

Main Methods:

• Performed detailed in silico quantum mechanical calculations of nitrenium cation formation energetics.
• Compiled the largest dataset to date comparing computational data with in vitro Ames test results.
• Utilized beanplots for statistical analysis and comparison with QSAR and knowledge-based methods.

Main Results:

• Demonstrated a strong correlation between calculated nitrenium ion formation energy and Ames test response.
• Presented a comprehensive dataset of in silico calculations versus in vitro data.
• Generated a watch-list of thousands of aryl-amines with calculated formation energies.

Conclusions:

• In silico calculation of nitrenium ion formation energy is a reliable predictor of mutagenicity for aryl-amines.
• This computational approach aids medicinal chemists in synthetic optimization and toxicity assessment.
• The study provides a valuable resource for identifying potentially mutagenic aryl-amines.