Tidying up after drugs
6 May 2011 by Evoluted New Media
Drug molecules are directed around the body via the bloodstream, but it’s important they don’t stay there, so the body has enzymes which ‘tidy up’ all foreign molecules.
Drug molecules are directed around the body via the bloodstream, but it’s important they don’t stay there, so the body has enzymes which ‘tidy up’ all foreign molecules.
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Binding orientation of dextromethaorphan in the active site of P450 Credit Julianna Olah |
Researchers from the University of Bristol have discovered how these enzymes work, which may help pharmaceutical chemists design better drugs.
Dr Julianna Olah – an EU Marie Curie Fellow – together with Professors Jeremy Harvey and Adrian Mulholland focussed on a class of enzymes which remove drug molecules from the body - cytochrome P450.
P450 is mainly situated in the liver and help ‘tidy up’ drug molecules by oxygenating them. The process usually works smoothly, but for some molecules it can lead to toxic oxygenated variants, while other molecules can interfere with the normal functioning of the enzyme. For these reasons, it’s necessary to understand how potential new medicines will react with P450 enzymes.
The researchers modelled the reaction mechanism of interaction between one specific drug –dextromethorpan, a component of some cough medicine – and one P450 variant.
“We carried out (a) molecular dynamics simulations, based on a molecular mechanics description of the system, of dextromethorphan bound to the active site of the 2D6 isoform of cytochrome P450, (b) electronic structure theory calculations of the energy barrier for the slow reaction step for oxidation of the aromatic ring and methoxy group of dextromethorphan using a model of the active site, (c) calculations using a combined quantum mechanical/molecular mechanics model to evaluate the energy barrier in the 2D6 isoform,” Harvey told Laboratory News.
“Our paper shows that calculations (a) and (b) suggest both oxidation pathways should compete – but (c) shows that aromatic oxidation cannot occur.”
Harvey said the outcome of the oxygen transfer process – which part of dextromethorphan oxygen gets added to – is affected by three factors. The first is the way in which the molecule fits into the enzyme (docking). The second is the intrinsic ability of each part of the molecule to accept oxygen. The third is how much each competing oxygen-delivery process is compatible with the shape of the enzyme pocket where the reaction occurs. The first two factors were already known, but the third was not. The discovery could help pharmaceutical chemists design new drug molecules with a better understanding of how they will be broken down in the body.
