Targeting challenging protein from integrin family

Utilizing Receptor.AI’s pocket detection workflow to target the ‘undruggable’ integrin family

~8M

compounds
screened

hit rate with 97 candidates

binding pockets
targeted

IC50 of 32 best hit compounds

dissociation constant of the top compound

Target is a heterodimeric receptor from the integrin family.
It is a promising target in immunological disorders and cancers.
There were no binding sites for small molecules known.
Also, no potent small molecule binders were known.
Target is often deemed undruggable by small molecules.
The goal is to design a strong binder to further optimize it into PPI disruptor.

Conformational changes predicted with crystal structures using AI-driven MD simulations.
Binding pockets identified within dynamic conformations by proprietary AI model.
Virtual screening of 8M stock library.
AI-docking with target-specific rescoring using ArtiDock.
In vitro ligand displacement assay performed to validate hit candidates’ ability to compete with a known ligand for binding.
SPR analysis performed to measure binding kinetics and affinity (dissociation constant — Kd).

Identified 97 hits out of ~1,200 hit candidates, resulting in  12% hit rate.
Identified 4 binding pockets, including one cryptic.
Successfully targeted 3 pockets - Pocket I (41 hits), Pocket II (40 hits), and Pocket III (16 hits).
32 hit compounds with IC50 < 10 μM.
The top hit shows the highest affinity (Kd = 0.35 μM).

*Pocket I visualization

*Pocket II visualization

*Pocket III visualization