The importance of hydrophobicity and electrophilicity descriptors in mechanistically-based QSARs for toxicological endpoints

Quantitative structure-activity relationship (QSAR) analysis of four toxicological data sets is described. The toxicological data include three data sets retrieved from the literature (the toxic and metabolic effects of 23 aliphatic alcohols on the perfused rat liver; the toxicity of 21 pyridines to mice; the lethality of 55 halogenated hydrocarbons to the mould Aspergillus nidulans ). In addition, the toxicity of 13 mono- and di-substituted nitrobenzenes in a 15 min assay using the alga Chlorella vulgaris was analysed. QSARs were developed successfully using descriptors to describe uptake in the organism (i.e. hydrophobicity as quantified by the logarithm of the octanol-water partition coefficient, log P ) and reactivity at the site of action (i.e. electrophilicity as quantified by the energy of the lowest unoccupied molecular orbital, E LUMO ). A further parameter describing molecular branching as also required to model the data for the aliphatic alcohols. The results demonstrate that mechanistically based QSARs can be developed for these diverse endpoints which are, in terms of statistical quality as good as, if not better, than QSARs based on less mechanistically interpretable descriptors.

Keywords:

• Toxicity
• Hydrophobicity
• Electrophobicity
• Qsar