RNA-binding protein which should be targeted by allosteric mechanism only to avoid unspecific off-target effects.
Only a few known allosteric inhibitors exist.
Two previously unknown allosteric binding pockets were identified by Receptor.AI's proprietary pocket detection AI model.
Pocket 2 and Pocket1 found by Receptor.AI
Methodology
Virtual Screening was performed for 1.4 million compounds from Enamine stock collection.
1000 ranked candidate compounds were prioritized.
209 of them were selected for experimental validation.
Results
The experimental validation was performed using a high throughput p110 knockout cell-based assay.
The criteria for a hit compound was established as a 5-fold increase in interferon induction compared to the control, with the desirable outcome being a 10-fold increase in interferon induction to surpass the efficacy of siRNA alternatives.
4 hit compounds with interferon inducing activities were identified.
Hit compounds were validated by the dose-response analysis.
Two of them exhibit comparable or superior maximal interferon induction with lower EC50 in comparison to a competing compound.
This was achieved on a much 2.5 times smaller screening library (209 against 500 for competitors).
Active scaffolds have been selected for further series expansion and optimization.
Dose-Response relationship for Compound 1, Compound 2 and Competitor Compound
Interferon induction observed at 25 uM for Receptor.AI hit compounds 1-4 obtained through virtual screening, a competitor small molecule, and ADAR1 siRNA
