An evaluation of ondansetron binding interactions with human cytochrome P450 enzymes CYP3A4 and CYP2D6.
The results of an evaluation study of ondansetron binding to human cytochromes P450 CYP3A4 and CYP2D6 is reported. The methodology includes NMR spectroscopic measurements of substrate to heme iron distances together with molecular modelling of the enzyme-substrate interactions. It is shown that there is a generally good agreement between the experimental and calculated binding affinities for ondansetron towards CYP2D6 and CYP3A4 enzymes, based on interactive docking studies. Moreover, the modelled binding orientations for ondansetron in CYP2D6 and CYP3A4 are largely consistent with the NMR data and with the known routes for P450-mediated metabolism of this compound.
Lewis
David F V
DF
Faculty of Health and Medical Sciences, University of Surrey, Guildford, Surrey, GU2 7XH, UK. d.lewis@surrey.ac.uk
Ito
Yuko
Y
Eddershaw
Peter J
PJ
Dickins
Maurice
M
Goldfarb
Peter S
PS
D019389:Cytochrome P-450 CYP2D6 / Q000378:metabolism*; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism*; D006418:Heme / Q000378:metabolism; D006801:Humans; D007501:Iron / Q000378:metabolism; D009682:Magnetic Resonance Spectroscopy / Q000379:methods; D008958:Models, Molecular; D017294:Ondansetron / Q000378:metabolism*; D011485:Protein Binding
D006418:Heme; D017294:Ondansetron; D007501:Iron; D019389:Cytochrome P-450 CYP2D6; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human