I have an active small molecule inhibitor of an enzyme.
The S enantiomer has IC50 0.5 µM.
The R enantiomer has IC50 1.1 µM.
But the racemic has IC50 2.4 µM (i.e. less active than both R and S).
Can it be explained by receptor-binding-difference or intra-competition among the individual enantiomers?
Racemic mixtures may have IC50 values higher than that of individual enantiomers if both enantiomers have affinities for the same target. Alternatively, a less potent enantiomer can enhance the inhibitory activity of the bioactive enantiomer (chiral switch effect)
Firstly, I would look at the error of the biological assay (just to be sure that the data obtained are statistically significant).
The other reason might be the synergy. Look at the literature, for example:
"Complementary and synergistic antinociceptive interaction between the enantiomers of tramadol" Article Complementary and synergistic antinoceptive interaction betw...
or
Article Pharmacological synergism of stereoisomers
The latter paper is dated 1929, so the case you posted could be a pretty known issue.
Oladoja A. Awofisayo
Thanks a lot. We think we might have negative synergism here. (Racemic is less active than both enantiomers.)
Can you please provide any supporting articles in this context?
Mateusz Mach
Thanks a lot. We will also recheck our IC50 values.
Is Negative Synergism for enantiomers that much common as that of Synergism?
When you consider an active drug, research is usually focused on increased potency (which may have a lot of advantages if the other chiral isomer is relatively non-harmful). So, there would be more examples of synergism than negative synergism (which is rather called antagonism).
But if the synergism of enantiomers (diastereoisomers) is possible, the other situation should be possible as well... :-)
Examples of antagonism can be found here:
An Introduction to Terminology and Methodology of Chemical Synergy—Perspectives from Across Disciplines:
https://www.frontiersin.org/articles/10.3389/fphar.2017.00158/full
or here:
Article Enantiomers and Their Resolution
(references, 2, 9-12)or
Article Stereochemistry in Drug Action
Another aspect when dealing with such issues is the optical purity of the isolated material, especially when there is a relatively high difference in potency between the respective optical antipodes; for example:
Article Steric aspects of agonism and antagonism at ?-adrenoceptors:...
...and some general summary:
Article Pharmacologial interactions: Synergism, or not synergism, th...
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