The impact of carbon-hydrogen bond dissociation energies on the prediction of the cytochrome P450 mediated major metabolic site of drug-like compounds.

Cytochrome P450 is a family of enzymes which is estimated to be responsible for over 75% of phase I drug metabolism. In this process carbon hydrogen bonds (C-H) are broken for hydroxylation indicating that the bond dissociation energy (BDE) plays a pivotal role. A host of experimentally derived C-H BDEs were benchmarked against their theoretical counterparts and an excellent correlation was found (R(2) = 0.9746, n = 100). The C-H BDEs were calculated for fifty drugs with known major hydrogen abstraction sites. Of those twelve (24%) had their major metabolic site at the lowest C-H BDE. The most prominent factor in determining the metabolic site is the presence of tertiary and secondary amine moieties (44%). Other features such as lipophilicity and steric accessibility of the pertinent molecular scaffolds are also important. Nevertheless, out of the 586 C-H BDEs calculated the average of the major hydrogen abstraction sites are statistically significantly lower by 6.9-12.8 kcal/mol (p-value = 7.257 × 10(-9)). This means that C-H BDEs are an indispensable component in building reliable models of first pass metabolism of xenobiotics.