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Contenuto archiviato il 2024-05-29

QM/MM modelling of human cytochrome P450 isoforms


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.

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