PMID- 16162012
OWN - NLM
STAT- MEDLINE
DCOM- 20051108
LR  - 20050915
IS  - 0022-2623 (Print)
IS  - 0022-2623 (Linking)
VI  - 48
IP  - 19
DP  - 2005 Sep 22
TI  - Metabolic regio- and stereoselectivity of cytochrome P450 2D6 towards 
      3,4-methylenedioxy-N-alkylamphetamines: in silico predictions and experimental 
      validation.
PG  - 6117-27
AB  - 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.
FAU - Keizers, Peter H J
AU  - Keizers PH
AD  - 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.
FAU - de Graaf, Chris
AU  - de Graaf C
FAU - de Kanter, Frans J J
AU  - de Kanter FJ
FAU - Oostenbrink, Chris
AU  - Oostenbrink C
FAU - Feenstra, K Anton
AU  - Feenstra KA
FAU - Commandeur, Jan N M
AU  - Commandeur JN
FAU - Vermeulen, Nico P E
AU  - Vermeulen NP
LA  - eng
PT  - Journal Article
PL  - United States
TA  - J Med Chem
JT  - Journal of medicinal chemistry
JID - 9716531
RN  - 0 (Amphetamines)
RN  - EC 1.14.14.1 (Cytochrome P-450 CYP2D6)
SB  - IM
MH  - Amphetamines/*chemistry
MH  - Cytochrome P-450 CYP2D6/*chemistry/genetics
MH  - Magnetic Resonance Spectroscopy
MH  - Models, Molecular
MH  - Mutation
MH  - Oxidation-Reduction
MH  - Quantitative Structure-Activity Relationship
MH  - Stereoisomerism
MH  - Substrate Specificity
EDAT- 2005/09/16 09:00
MHDA- 2005/11/09 09:00
CRDT- 2005/09/16 09:00
PHST- 2005/09/16 09:00 [pubmed]
PHST- 2005/11/09 09:00 [medline]
PHST- 2005/09/16 09:00 [entrez]
AID - 10.1021/jm050338+ [doi]
PST - ppublish
SO  - J Med Chem. 2005 Sep 22;48(19):6117-27. doi: 10.1021/jm050338+.