Researchers piece together molecule breakdown puzzle
In a new study, EU—funded researchers have unlocked the mystery behind the breakdown of molecules in the body. This latest finding will lead to the development of new and improved drugs. The study was backed in part by the MODELLING CYPS ('QM/MM modelling of human cytochrome P450 isoforms') project, which received a Marie Curie Intra—European Fellowships (EIF) grant worth almost EUR 161 000 under the EU's Sixth Framework Programme (FP6). The results are presented in the journal Proceedings of the National Academy of Sciences.
In cooperation with Professors Jeremy Harvey and Adrian Mulholland of the School of Chemistry at Bristol University in the UK, EU Marie Curie Fellow Dr Julianna Olah probed a class of enzymes called cytochromes P450. Experts say these enzymes are involved in the removal of drug molecules from the body.
When patients consume a tablet of medicine, the bloodstream absorbs the active molecules through the gut, and the molecules travel around the body, reaching the cells that are targeted. But experts say they are not supposed to remain within the body forever. Enzymes help break down the active molecules in order to make excretion possible, thus 'tidying' up the process.
The cytochromes P450 are such 'tidying up' enzymes. They have evolved over the years to handle all 'foreign' compounds that the normal metabolism fails in breaking down, including proteins, lipids or carbohydrates.
The team said the P450 enzymes are located primarily in the liver, and support drug molecule removal by adding oxygen to them. While the process works for the most part, most of the time, some cases result in oxygenated variants that are toxic. Other molecules could also interfere with the normal function of the P450 enzymes.
Increased knowledge about how a given molecule reacts with these enzymes is key, and the Bristol team helps in this quest by modelling the reaction mechanisms for interaction between one specific drug (dextromethorphan) and one P450 variant.
'Our calculations showed that the outcome of the oxygen transfer process (i.e. which part of dextromethorphan oxygen gets added to) is affect by three factors,' Professor Harvey points out. '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,' he adds.
'While these first two factors were already known, the third was not. This discovery can help pharmaceutical chemists design new drug molecules with a better understanding of how they will be broken down in the body.'