Rational design of GPCR biased Ligand

GPCR is one of druggable target. GPCR activation controls many networks of signaling pathways, which for most receptors are mediated by both G proteins and beta-arrestins. Different signaling pathways give different effects. To avoid side effects from G protein signals, designing beta-arrestins selective ligand is useful strategy for drug discovery. And there are lots of reports about biased-ligand from a few years ago.

I am interested in these area and following article found.
“structure-inspired design of b-arrestin-biased ligands for aminergic GPCRs”

The authors design selective biased ligand of D2 receptor by using homology modeling/SBDD and MD.

At first they focused in to TM5 and EL2 region where are important for G protein/beta arrestin selectivity. And design new molecule from Aripiprazole, replace from di-chloro to indole moiety (Compound 1). The compound 1 was biased.
Next they tried to design substituted analogue of compound1 and got clear SAR of the substituents. Also they performed MD simulation about the indole motif and revealed the effect of the substituents.

Finally they could rationally design more selective biased ligand than initial compound 1 Fig5. Bias index is 20 vs 2 (compound7 vs compound1)

It was interesting for me because all molecules have quite similar structure but little difference affect protein-ligand contacts and can control their signaling pathway!

And computational approach helps rational biased drug design. I feel Low-molecular drug discovery is still exciting area of science.

BTW, in the article Aripiprazole is used for starting point.
Aripiprazole is one of major drug for schizophrenia and bipolar disorder. And Rexulti is also approved drug for schizophrenia and major depression. Structural difference of these molecules is a tail part, di chloro benzene or benzothiophene.

These compounds show different pharmacological profiles.
Also there are difference in metabolic profiles.
Receptor Rexulti Abilify(Ki nM)
5-HT1A 0.12 5.6
5-HT2A 0.47 8.7
5-HT2B 1.9 0.4
D2 0.3 1.6
D3 1.1 5.4
H1 19 27.9
a1b 0.17 34.4
a2c 0.59 37.6

I am now interested in the patent strategy. I will check it.


Published by iwatobipen

I'm medicinal chemist in mid size of pharmaceutical company. I love chemoinfo, cording, organic synthesis, my family.

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