A new method to test the likelihood of a drug turning into a potentially harmful version of itself when it enters the body has been developed by researchers at Cardiff University.
The novel approach that assesses the likely risk of a drug undergoing racemization was developed in collaboration with scientists at Liverpool John Moores University and AstraZeneca and published recently in Angewandte Chemie.
The research team believes the new method could potentially lead to a significant reduction in the financial risk associated with drug development by identifying at-risk drug candidates early on in the production process.
Drug compounds often exist in either a right- or left-handed form, with both forms having an identical chemical composition but a structure that is a non-superimposable mirror image of one another. These compounds are known as enantiomers. Drugs can contain both right- and left-hand versions of a compound, but often only one of a drug's enantiomers is responsible for the desired physiologic effects, while the other enantiomer is less active, inactive, or can sometimes produce adverse effects.
The most famous example of this is thalidomide, which was withdrawn from the market when it was found to cause birth defects. One enantiomer caused the desirable sedative effects, while the other enantiomer caused the birth defects. Since the thalidomide crisis, drug developers have strived to create drugs containing only one enantiomer.
However, it's possible that a single enantiomer can rapidly flip to the mirror image of itself when it enters the body, as a result of racemization. This transformation is thought to be caused by the drug's interaction with basic compounds in the water in the body.
In their study, the team set up experiments in which they simulated the chemical conditions of the human body and introduced a number of drugs to the system, monitoring the rate at which the different drugs underwent racemization using circular dichroism and NMR spectroscopy. Using these results, they were able to generate a simple mathematical model that could quickly predict the rate of racemization in any drug compound, subsequently indicating how safe and productive that drug would be if administered.
"We believe that this risk-assessment will make it possible to manufacture safer medication by helping the pharmaceutical industry to quickly spot medication that will fail during development and focus their efforts on compounds that are more likely to work," lead author Niek Buurma explained.