The Quantitative Structure-Mutagenicity Relationship of Polycylic Aromatic Hydrocarbon Metabolites

Abstract

Quantitative structure-activity relationships (QSARs) for benz [a]anthracene (BA) mutagens using 73 descriptors were searched. The mutagenicity data was obtained from Ames assays for Mycobacterium vanbaalenii, Mycobacterium gilvum and Mycobacterium flavescens strains. These data were fitted using a mutagenicity-cytotoxicity competition model which defines the mutagenic potencies of BA metabolites, and include oxides, phenols, quinones, and dihydrodiols. The QSAR equations were derived using the molecular descriptor set (charged partial surface area, spatial, thermodynamic and electronic descriptors) and semi-empirical energetic and charge descriptors. Genetic function approximation was used to reduce and fit independent variables, including linear-and quadratic-based functions. Multiple QSAR equations were generated and a separate QSAR equation was chosen and evaluated for each strain using conventional r2, F-test, and crossvalidated r2. Each strain exhibited its own characteristic descriptors.

QSAR studies on peptide α-ketoamides and α-ketohydroxamate derivatives as calpain I inhibitors

“…Compounds 4, 6 and 16 (Table II) has standardized residuals 2.502, 2 2.004 and 2 2.778, respectively, and can safely be excluded from the data set. Outliers were removed in order to obtain the best statistical result [26].…”

Statistical treatment of cytotoxicity in Ames bacterial reverse mutation assays can provide additional structure–activity relationship information

“…[15][16][17][18][19] It is noteworthy that the QSAR equations for the mutagenicity and cytotoxicity of quinolines demonstrate very different relationships. 7,[20][21][22][23] For the mutagenicity of these quinolines, both hydrophobic and steric interactions appear to be important. In contrast, the cytotoxicity is mainly affected by increasing hydrophobicity and by the addition of electron-withdrawing substituents to the quinoline ring.…”

A Classification Model to Identify Direct-Acting Mutagenic Polycyclic Aromatic Hydrocarbon Transformation Products

“…A search for existing studies on QSAR development for environmental PAH TPs uncovered seven studies that contained QSAR relationships for specific subcategories of PAHs (Figure and Table ). ,,,,− These studies were used to inform the types of descriptors that were likely to be helpful in predicting PAH mutagenicity. The highest occupied molecular orbital and lowest unoccupied molecular orbital energies (ϵ- HOMO and ϵ- LUMO , respectively), the ϵ-HOMO-ϵ-LUMO gap, the ionization potential, and electron affinity were calculated using electronic structure calculations in Gaussian 09 .…”

“…From the relaxed structures, vertical ionization potentials and electron affinities were calculated with single-point energy calculations (in positive and negative charge states, respectively). The gas phase was used to be consistent with the National Institutes of Standards and Technology (NIST) data, the gold standard reference, and previous studies that used energetic data. ,, Pharmaceutical Data Exploration Laboratory (PaDEL)-Descriptor was used to calculate topological descriptors for the Ames test datasets. The coordinates from the DFT optimization were supplied to PaDEL-Descriptor for use in the calculation of three-dimensional descriptors.…”