title: Trends in predicted chemoselectivity of cytochrome P450 oxidation: B3LYP barrier heights for epoxidation and hydroxylation reactions.
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.
authors.affiliation: Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Universitetsparken 2, DK-2100 Copenhagen, Denmark.
authors.forename: Patrik
authors.initials: P
authors.lastname: Rydberg
authors.affiliation: Centre for Computational Chemistry, School of Chemistry, University of Bristol, Cantock's Close, Bristol BS8 1TS, United Kingdom.
authors.forename: Richard
authors.initials: R
authors.lastname: Lonsdale
authors.affiliation: Centre for Computational Chemistry, School of Chemistry, University of Bristol, Cantock's Close, Bristol BS8 1TS, United Kingdom.
authors.forename: Jeremy N
authors.initials: JN
authors.lastname: Harvey
authors.affiliation: Centre for Computational Chemistry, School of Chemistry, University of Bristol, Cantock's Close, Bristol BS8 1TS, United Kingdom.
authors.forename: Adrian J
authors.initials: AJ
authors.lastname: Mulholland
authors.affiliation: Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Universitetsparken 2, DK-2100 Copenhagen, Denmark. Electronic address: lo@sund.ku.dk.
authors.forename: Lars
authors.initials: L
authors.lastname: Olsen
mesh_terms: D002110:Caffeine / Q000737:chemistry; D053138:Cyclohexenes / Q000737:chemistry / Q000378:metabolism; D003577:Cytochrome P-450 Enzyme System / Q000737:chemistry* / Q000378:metabolism*; D004852:Epoxy Compounds / Q000378:metabolism*; D006900:Hydroxylation; D008958:Models, Molecular; D010084:Oxidation-Reduction; D013816:Thermodynamics
chemical_list: D053138:Cyclohexenes; D004852:Epoxy Compounds; D002110:Caffeine; D003577:Cytochrome P-450 Enzyme System
keywords: Aliphatic hydroxylation; B3LYP; Density functional theory; Dispersion; Epoxidation