I have synthesized a racemic compound and its two enantiomers. The IC50 value of racemic compound is 2.4 μM, for R is 1.1 μM and for S is 0.5 μM against the target protein. How to explain the difference in activity?
The compounds were synthesized from commercially available racemic, R and S enantiomers.
Thanks in advance.
In your case, one enantiomer (S) is doubly active than the other. By mixing them equally, it seems both of them have the same "binding probability" with the target receptor but with different responses. So, the binding of the less active enantiomer could reduce the activity of the most active enantiomer by a half as you observed. Because its contact with the receptor has been also divided by two.
Concur; I would investigate receptor binding of each separately, if Kd are also different is supports the hypothesis
Firstly, I would say thanks to Eitel Ngoh Misse Mouelle and Michael Coote for your answer. additionally I would like to request you can you provide few article as a evidence so that I can go through these.
start here:
Binding of. DELTA.-and. LAMBDA.-[Ru (phen) 3] 2+ to [d (CGCGATCGCG)] 2 studied by NMR
Magdalena Eriksson, Mikael Leijon, Catharina Hiort, Bengt Norden, Astrid Graeslund
Biochemistry 33 (17), 5031-5040, 1994
https://doi.org/10.1038/s41598-018-19202-7. I think this paper could help.
If you can't perform an experiment as the abovementioned paper, you can try in silico means like molecular docking and molecular Dynamic in order to find the value of K related with each enantiomer.
Thank you everyone. Eitel Ngoh Misse Mouelle I did molecular docking. But there almost same type of docking conformation is coming. That's why it makes me more confusion.
Unless your protein has kind of allosteric binding sites, I would expect these differences originate from the measurement errors. Even in the case of good assays, expected uncertainty would be about +-5% in the scale of log IC50-s. Repeat the measurements!
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