We are trying to optimize selectivity of a chemical series for one protein isoform over other isoforms, with ours having a unique charged amino-acid residue not present in other isoforms.
Is anyone aware of such examples where well-designed analogs capable of capturing an ion-dipole interaction (rather than by covalent binding) led to a boost in selectivity/potency? Thanks.
I think this articles can help you.
Physical basis of specificity and delayed binding of a subtype selective sodium channel inhibitor (https://www.nature.com/articles/s41598-018-19850-9)
At Long Last Potent and Selective KDM5 Inhibitors
(Article At Long Last Potent and Selective KDM5 Inhibitors
)
Hi Sylvain,
I could recommend our last two papers about Meprin inhibitors. Addressing an arginine present only in one isoform (Tyr in the other) led to a favorable selectivity.
Regards
Daniel
10.1002/cmdc.201800300
10.1021/acs.jmedchem.8b00330
Thanks for all the suggestions! The Nav1.7 article with the MD simulation explaining why these cpds exhibit show slow binding kintetic is very interesting. Daniel, I hope to be able to read your articles soon!
In our case, one hypothesis is the possible interaction between a charge amino acid residue and a dipole (not charged) ligand (small molecule). We postulated an ion-dipole interaction but i am not aware of examples where optimizing such interactions led to significant boost in potency and/or selectivity. Tweaking the dipole of our scaffold could improve the electrostatic complementary for the desired isoform but could this also lead to preferred shape complementary over other isoforms?
Comments/suggestions are welcomed!!
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