Quantum-Mechanical Studies of Reactions Performed by Cytochrome P450 Enzymes

Abstract

We review density functional theory studies of various types of reactions performed by the cytochrome P450 family of enzymes. We describe the various reactions on equal footing with an emphasisis on models to predict sites of metabolism for an arbitrary molecule. The activation barriers range between 0 and 109 kJ/mol, depending more on the atoms surrounding the reactive site than on the type of reaction. Therefore, the intrinsic reactivity can rather well be predicted by simple chemical rules. However, for a full predictive model, the steric effects of the enzyme surrounding the heme group need also to be modeled, which often is harder.

Mechanism of the N-Hydroxylation of Primary and Secondary Amines by Cytochrome P450

“…The most common product that is generated from tertiary amines results from N -dealkylation; however, for some amines the N -oxide is formed as well . The mechanism for the reactions leading to these two products, and the competition between them, has been investigated in several studies during the past few years. − However, for primary and secondary amines, the oxidation of the nitrogen atom does not lead to the formation of an N -oxide but to the hydroxylamine. It is important to understand the mechanism of hydroxylamine formation, as it has been shown that hydroxylamines formed from primary arylamines may be carcinogenic, while the ones formed from secondary alkylamines may lead to mechanism-based inhibition of CYP enzymes .…”

WhichCyp: prediction of cytochromes P450 inhibition

“…These enzymes are involved in the metabolism of a large majority of the drugs in use today (Guengerich, 2006). Modeling of their interactions with druglike compounds have been a hot topic during the past decade, stretching from quantum mechanical studies of reaction mechanisms to data mining approaches and QSAR studies (Carlsson et al, 2010;Kirchmair et al, 2012;Rydberg et al, 2012).…”

Reactive Metabolites from Thiazole-Containing Drugs: Quantum Chemical Insights into Biotransformation and Toxicity

“…To mimic CYPs, the model species Cpd I was used as the model oxidant, , which is an iron (IV-oxo) radical cation with heme-porphine with SH – at the axial position. This model has been accepted by various scientific groups to provide reasonably accurate energy estimates for CYP-catalyzed metabolic studies. − For this study, the multistate reactivity (both doublet and quartet states) of Cpd I was considered. The geometry optimization of all of the intermediates on the metabolic path of TZ leading to MBI were performed using the hybrid density functional (DFT) method B3LYP, with a basis set 6-31+G­(d) − (except Fe) and LanL2DZ basis set on the Fe center.…”