Novel Tool to Test Likelihood of Drugs Going Rogue on Entering the Body
Racemisation has a large impact upon the biological properties of molecules but the chemical scope of compounds with known rate constants for racemisation in aqueous conditions was hitherto limited. To address this remarkable blind spot, a team of researchers at the Cardiff University in collaboration with their counterparts at Liverpool John Moores University and AstraZeneca, have now developed a simple test to elucidate the likelihood of a drug turning into
a potentially harmful version of itself when it enters the body.Unfortunately, despite attempts by pharma companies to make only the active and desired enantiomer for a drug it is possible for racemisation to occur once the drug enters the body and thus form the inactive or potentially dangerous enantiomer form. This is not only impactful on the health of the patient but also carries a financial implication to the drug developer.
The most famous example of this is thalidomide, which was withdrawn from the market when it was found to cause birth defects.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.
“Following the thalidomide disaster, researchers worldwide have focussed on making compounds enantioselectively — that is containing just one enantiomer,” explained Dr Niklaas Buurma, from Cardiff University’s School of Chemistry, lead author of the study. “However, while compounds are routinely tested to ensure they are inherently stable under physiological conditions, not much thought has been given as to how to prevent configurational instability at the design stage, using suitable predictive models.”
The researchers have developed a simple approach to trawl through large databases of pharmaceutical drugs and assess the likely risk of a drug undergoing racemisation – a process in which a drug flips into a mirror image of itself and becomes either inert or potentially dangerous.
The collaborative work, the team set up experiments to simulate the chemical conditions of the human body and then introduced a number of drugs to the system, monitoring the rate at which the different drugs underwent racemisation.
From their results, the team were able to generate a simple mathematical model that could quickly predict the rate of racemisation in any drug compound, subsequently indicating how safe and productive that drug would be if administered. This is the first time an assessment tool for this purpose has been developed.
“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,” added Buurma.
