Targeting challenging protein from integrin family
Addressing difficult-to-target binding pockets and discovering potential binders
Background
Heterodimeric receptor from integrin family involved in protein-protein interactions (PPIs).
Promising for immunological disorders, inflammation and cancers.
No binding sites for small molecules are known.
No potent small molecules binders exist.
Challenging target, often deemed undruggable by small molecules.
Methodology
MD simulations of the full-length dimer to produce an ensemble of protein conformations.
Receptor.AI pocket detection pipeline revealed 4 tentative binding pockets including one cryptic pocket.
Stock ~5M chemicalspace used.
Two screening tracks for each pocket (considering binding sites with cations):AI-based initial virtual screening followed by ArtiDock AI docking.
Direct ArtiDock AI docking of ~100k cluster centres.
~500 hit candidates provided for experimental validation.
Protein ligand in vitro displacement assay used.
Project workflow
Results
51 hit compounds obtained (~10% hit rate).
Potency range 10-100 μM in displacement assay.
Experimental validation included single concentration primary assessment and dose response measurements for initial hits.
Extremely diverse hits: 49 distinct Murcko assemblies out of 51 hits → diverse pool of scaffolds for subsequent optimization.
Four previously unknown prospective binding pockets for small molecules are identified using Receptor.AI pocket detection workflow.
Three of them are targeted by experimentally validated hits:
Pocket I: 14 hits
Pocket II: 30 hits
Pocket III: 7 hits
Multiple mechanism of action are likely to be triggered by the binders in different pockets → High flexibility and robustness in subsequent discovery stages.
Spatial representations of three binding pockets targeted by hit compounds
