Mirror, Mirror…
A tool to predict racemization could help prevent drug discovery dead ends
Many drugs are chiral molecules, which means that they have the potential to “flip” and exist as different enantiomers – non-superimposable mirror images of the original molecule with an identical chemical structure. In some cases, this flipping behavior can occur when an enantiomerically pure drug enters the body – a process known as racemization. Recent research aims to predict racemization (1), so we spoke to co-author Niek Buurma from Cardiff University’s School of Chemistry to discover more about the dangers of mirror molecules – and a new tool to remedy the problem.
Why is racemization a problem?
The pharmaceutical action of a significant fraction of all drugs depends on administering the correct enantiomer. When we administer a mixture of enantiomers, one of the enantiomers will act as intended, but the other doesn’t fit with the target, which can lead to binding to unintended targets and potentially serious side effects. If racemization is discovered late in the drug discovery process, the compound may turn into an expensive blind alley.
These days, everyone is aware of the need to administer single-enantiomer drugs. But until now, there were no good models to quantitatively predict how these enantiomers would behave once exposed to the aqueous conditions in the body.
How can your model help?
Using circular dichroism and H NMR spectroscopy to measure the kinetics for racemization of 28 compounds, we (along with Andrew Leach, from Liverpool John Moores University) have developed a predictive model that allows efficient quantitative prediction of racemization risk. Essentially, it allows researchers in academia and industry to identify molecules at risk of racemization at a very early stage. Not only does this help avoid dead-end research and development pathways, but it also allows researchers to “design out” racemization risk by exploring the effect of changes to the molecular structure. In addition, we present a series of different experimental approaches to confirm whether a potential drug racemizes under physiological conditions.
What’s next?
We are now developing a version of the model that predicts the risk of racemization during typical reaction workup procedures. Our guidelines and predictive models provide a solid approach to predicting racemization, and we would like to see our quantitative predictions and experimental tests incorporated as standard in the drug discovery pipeline.
- A Ballard et al., “Quantitative prediction of rate constants for aqueous racemization to avoid pointless stereoselective syntheses”, Angew Chem Int Ed, 57, 982 (2018).
I have an extensive academic background in the life sciences, having studied forensic biology and human medical genetics in my time at Strathclyde and Glasgow Universities.
