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 (CeH) are broken for hydroxylation indicating
that the bond dissociation energy (BDE) plays a pivotal role. A host of experimentally derived CeH BDEs were benchmarked against their theoretical counterparts and an excellent correlation was found (R2 ¼ 0.9746, n ¼ 100). The CeH BDEs were calculated for fifty drugs with known major hydrogen abstraction sites. Of those twelve (24%) had their major metabolic site at the lowest CeH 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 CeH BDEs calculated the average of the major hydrogen abstraction sites are statistically significantly lower by 6.9e12.8 kcal/mol (p-value = 7.257 x 10 -9). This means that CeH BDEs are an indispensable component in building reliable models of first pass metabolism of xenobiotics.