Trillion-compound docking finds new GPR119 chemotypes, confirmed by cryo-EM
- V-SYNTHES2 screened roughly three trillion on-demand Enamine compounds against the orphan GPCR GPR119, yielding several new agonist and antagonist chemotypes.
- Analog-by-catalog expansion and stereoselective synthesis gave full and partial agonists with low-micromolar potency.
- Cryo-EM structures of Gs-bound GPR119 with three hits matched the docking poses and added SAR detail, leading to two improved agonists.
💡 Points Based on the abstract
The experimental structures matching the predicted poses is the strongest part; docking hit rates against lipid-binding GPCRs are often inflated by greasy compounds. Low-micromolar agonists are still far from a lead, though, and GPR119's clinical record is poor. I'd check lipophilicity and ligand efficiency of the hits before investing in them.
📄 Paper · bioRxiv ↗ Structure-based discovery of new GPR119 ligands from on-demand tera-scale chemical space