title: Metabolic regio- and stereoselectivity of cytochrome P450 2D6 towards 3,4-methylenedioxy-N-alkylamphetamines: in silico predictions and experimental validation.
abstract: A series of 3,4-methylenedioxy-N-alkylamphetamines (MDAAs) were automatically docked and subjected to molecular dynamics (MD) simulations in a cytochrome P450 2D6 (CYP2D6) protein model. The predicted substrate binding orientations, sites of oxidation, and relative reactivities were compared to the experimental data of wild-type and Phe120Ala mutant CYP2D6. Automated docking results were not sufficient to accurately rationalize experimental binding orientations of 3,4-methylenedioxy-N-methylamphetamine (MDMA) in the two enzymes as measured with spin lattice relaxation NMR. Nevertheless, the docking results could be used as starting structures for MD simulations. Predicted binding orientations of MDMA and sites of oxidation of the MDAAs derived from MD simulations matched well with the experimental data. It appeared the experimental results were best described in MD simulations considering the nitrogen atoms of the MDAAs in neutral form. Differences in regioselectivity and stereoselectivity in the oxidative metabolism of the MDAAs by the Phe120Ala mutant CYP2D6 were correctly predicted, and the effects of the Phe120Ala mutation could be rationalized as well.
authors.affiliation: Leiden Amsterdam Center for Drug Research (LACDR)/Division of Molecular Toxicology and Division of Organic and Inorganic Chemistry, Department of Chemistry and Pharmacochemistry, Vrije Universiteit, De Boelelaan 1083, 1081 HV Amsterdam, The Netherlands.
authors.forename: Peter H J
authors.initials: PH
authors.lastname: Keizers
authors.forename: Chris
authors.initials: C
authors.lastname: de Graaf
authors.forename: Frans J J
authors.initials: FJ
authors.lastname: de Kanter
authors.forename: Chris
authors.initials: C
authors.lastname: Oostenbrink
authors.forename: K Anton
authors.initials: KA
authors.lastname: Feenstra
authors.forename: Jan N M
authors.initials: JN
authors.lastname: Commandeur
authors.forename: Nico P E
authors.initials: NP
authors.lastname: Vermeulen
mesh_terms: D000662:Amphetamines / Q000737:chemistry*; D019389:Cytochrome P-450 CYP2D6 / Q000737:chemistry* / Q000235:genetics; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D009154:Mutation; D010084:Oxidation-Reduction; D021281:Quantitative Structure-Activity Relationship; D013237:Stereoisomerism; D013379:Substrate Specificity
chemical_list: D000662:Amphetamines; D019389:Cytochrome P-450 CYP2D6