Trends in predicted chemoselectivity of cytochrome P450 oxidation: B3LYP barrier heights for epoxidation and hydroxylation reactions

Patrik Rydberg, Richard Lonsdale, Jeremy N. Harvey, Adrian J. Mulholland, Lars Olsen*

*Corresponding author for this work

Research output: Contribution to journalArticle (Academic Journal)

17 Citations (Scopus)

Abstract

Prediction of epoxide formation in drug metabolism is a difficult but important task, as epoxide formation is linked to drug toxicity. A comparison of the energy barriers for cytochrome P450 mediated epoxidation of alkenes to the barriers for the hydroxylation of an aliphatic carbon atom next to a double bond has been performed using B3LYP and B3LYP-D3. Relevant experimental data on oxidation selectivity has also been assessed. The results show that density functional theory, when using B3LYP-D3, does well in reproducing the experimental trends. Considering that the comparison involves chemical steps with quite different features this is remarkable. We also find that B3LYP consistently underestimates the hydrogen abstraction barriers relative to the epoxidation barriers, and that including a dispersion correction reduces this problem. © 2014 Published by Elsevier Inc.

Original languageEnglish
Pages (from-to)30-35
Number of pages6
JournalJournal of Molecular Graphics and Modelling
Volume52
DOIs
Publication statusPublished - Jul 2014

Keywords

  • Aliphatic hydroxylation
  • B3LYP
  • Density functional theory
  • Dispersion
  • Epoxidation

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