Do Fukui function maxima relate to sites of metabolism? A critical case study

The usefulness of local reactivity descriptors for understanding drug metabolism is investigated. Electrophilic Fukui functions are calculated for 18 drugs and 11 agrochemicals and their relation to experimentally observed metabolites is discussed. Maxima of the Fukui functions correspond to major sites of metabolic attack in many examples, facilitating a posteriori understanding of experimental findings. In the second part of the paper, the nature of the electrophilic oxidant species in cytochromes, called Compound I (Cpd I), is investigated within the Fukui framework. Nucleophilic Fukui functions are calculated involving the relevant spin states of Cpd I, allowing a more qualitative, intuitive understanding of its reactivity.