Abstract Details


Poster 37: Modeling Species Selectivity in Rat and Human Cytochrome P450 2D Enzymes

Grace Edmund1, Brendan Howlin1, Dave Lewis1
1University of Surrey
Cytochrome P450 enzymes (CYP450) are central to drug metabolism, carrying out the metabolism of 75% of known drugs in current clinical use. Important effects such as adverse drug reactions and genetically determined differences in drug toxicity and efficacy depend on CYP450 activity, yet this cannot be easily predicted from protein structures alone and is often found through the use of animal models.

Updated models of the Rat Cytochrome P450 2D enzymes have been produced based on the recent x-ray crystal structures of the Human P450 2D6 enzymes both with and without a ligand bound. The differences in species selectivity between the epimers quinine and quinidine are rationalised using these models and the results discussed with regard to previous studies.

The x-ray structure of the enzymes with a ligand bound is shown to be a better model for explaining the observed experimental binding of quinine and quinidine. Hence models with larger closed binding site are recommended for comparative docking studies. This is consistent with moelcular recognition in Cytochrome P450 enzymes being the result of a number of non-specific interactions in a large binding site.

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