期刊
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
卷 56, 期 -, 页码 48-55出版社
ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
DOI: 10.1016/j.ejmech.2012.08.017
关键词
Drug metabolism; Cytochrome P450; Density functional theory (DFT); Bond dissociation energy (BDE); Drug development/discovery
资金
- NeSI
- Ministry of Science Innovation
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 x 10(-9)). This means that C-H BDEs are an indispensable component in building reliable models of first pass metabolism of xenobiotics. (C) 2012 Elsevier Masson SAS. All rights reserved.
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