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 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 that 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.