Objective The research proposal focuses on the modeling of human cytochrome P450 (CYP) enzymes. CYPs protect organisms against xenobiotics, metabolize drugs and play an essential role in the biosynthesis of steroid hormones.Despite the fact that CYPs metabolize more than 90% of the drugs in man, the molecular basis of their catalytic activity is not understood yet. Our project aims to apply the most recent developments of computational chemistry, state-of-art QM/MM methods to address fundamental questions related to the activity of CYPs.- Inhibition: Bergamottin, one of the major furanocoumarins found in grapefruit juice, is an effective mechanism-based inhibitor of CYP3A4. Our aim is to elucidate the exact reaction mechanism of inhibition/inactivation of CYP3A4 by bergamottin. - Substrate and regioselectivity. CYP enzymes possess an overlapping substrate selectivity but with strong regioselectivity. We plan to compare the reactivity of CYP2D6 and CYP3A4 by modelling the metabolism of Dextromethorphan by the two isoforms.- Polymorphism. CYPs have various alleles, and the different variants of the enzyme display significant differences in activity which is directly related to differences in the metabolism of drugs among individuals.This has serious implications on the effective drug dose needed to treat patients. Quantum chemistry allows us to perform mutations on the enzyme in silico and our goal is to model and compare the reactivity of the wild-type enzyme (CYP2D6-wt), the CYP2D6-E mutant with no activity, an d the CYP2D6-J mutant with reduced activity.Our project is considered to be highly important in European dimensions and it will deliver added value to the whole community from the following points of view- as a part of the Structuring European Research Area- in relation to the regional policy of the EU- by promoting European science. Fields of science natural sciencesphysical sciencesquantum physicsnatural scienceschemical scienceselectrochemistryelectrolysisnatural scienceschemical sciencesphysical chemistryquantum chemistrynatural sciencesbiological sciencesgeneticsmutationnatural sciencesbiological sciencesbiochemistrybiomoleculesproteinsenzymes Keywords cytochrome P450s grapefruit juice components inhibition modelling polymorphism Programme(s) FP6-MOBILITY - Human resources and Mobility in the specific programme for research, technological development and demonstration "Structuring the European Research Area" under the Sixth Framework Programme 2002-2006 Topic(s) MOBILITY-2.1 - Marie Curie Intra-European Fellowships (EIF) Call for proposal FP6-2005-MOBILITY-5 See other projects for this call Funding Scheme EIF - Marie Curie actions-Intra-European Fellowships Coordinator THE UNIVERSITY OF BRISTOL EU contribution No data Address Senate House, Tyndall Avenue BRISTOL United Kingdom See on map Links Website Opens in new window Total cost No data
