ddE quantum-chemistry index with filters cuts false mutagenicity calls on 1,177 aromatic amines

Researchers using data from 16 laboratories described a refined way to predict the mutagenicity of primary aromatic amines (PAAs). The approach combines a quantum-chemistry index, ddE, with molecular weight and ortho-substitution filters. The work was published in Genes and Environment. The dataset covered 1,177 PAAs: 420 from public databases and 757 from in-house databases biomedcentral.comGenes and Environmentbiomedcentral.comOpen source ↗.

Standard QSAR systems, both knowledge-based and statistics-based, give low positive predictive values (PPV) for PAAs. Earlier studies suggested that PAAs are metabolized into genotoxic nitrenium ions. ddE is a relative-energy index derived from quantum chemistry calculations that measures the stability of these ions, and it has been correlated with mutagenicity.

Dataset and ddE calculation

The dataset included 465 Ames test-positive and 712 test-negative chemicals. For the in-house compounds, the authors scrutinized detailed Ames test data and made final decisions using common evaluation criteria. The ddE values were calculated with a convenient and consistent protocol.

Cutoff, filters and prediction scores

The best result came from a ddE cutoff of -5 kcal/mol combined with a molecular weight of 500 or less and the presence of ortho substitution groups. This gave a sensitivity of 72.0%, a specificity of 75.9%, a PPV of 65.6%, a negative predictive value of 80.9% and a balanced accuracy of 74.0% biomedcentral.comGenes and Environmentbiomedcentral.comOpen source ↗.

The PPV of the ddE-based approach was greatly reduced by the presence of two ortho substituent groups of ethyl or larger. Almost all such compounds were negative in the Ames test regardless of their ddE values. The authors suggest steric hindrance affecting interactions between the PAA and metabolic enzymes as the probable cause.

The great majority of PAAs with a molecular weight above 500 were also Ames-negative, although their ddE values predicted positive mutagenicity.

The authors conclude that combining molecular weight, ortho substitution patterns and ddE values minimizes false positives. In their view, this gives a more reliable basis for evaluating the genotoxic potential of PAAs biomedcentral.comGenes and Environmentbiomedcentral.comOpen source ↗.