title: An evaluation of ondansetron binding interactions with human cytochrome P450 enzymes CYP3A4 and CYP2D6.
abstract: 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.
authors.affiliation: Faculty of Health and Medical Sciences, University of Surrey, Guildford, Surrey, GU2 7XH, UK. d.lewis@surrey.ac.uk
authors.forename: David F V
authors.initials: DF
authors.lastname: Lewis
authors.forename: Yuko
authors.initials: Y
authors.lastname: Ito
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Eddershaw
authors.forename: Maurice
authors.initials: M
authors.lastname: Dickins
authors.forename: Peter S
authors.initials: PS
authors.lastname: Goldfarb
mesh_terms: 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
chemical_list: D006418:Heme; D017294:Ondansetron; D007501:Iron; D019389:Cytochrome P-450 CYP2D6; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human