Trillion-compound docking screen finds new GPR119 agonist chemotypes, validated by cryo-EM structures
- Docking about three trillion make-on-demand Enamine compounds with V-SYNTHES2 against recent lipid-bound GPR119 structures surfaced several new agonist and antagonist chemotypes.
- Analog-by-catalog expansion and stereoselective synthesis gave full and partial agonists with low-micromolar activity in cell-based assays.
- Cryo-EM structures of GPR119-Gs with three hits matched the docking poses, informed SAR, and led to two optimized agonists, BRI-17403 and BRI-17409.
💡 Points Based on the abstract
Low-micromolar hits are early days, and GPR119 has a history of potent, greasy agonists that stalled clinically, so lipophilicity and ligand efficiency deserve a look before any excitement. The cryo-EM poses are the valuable part: they let a team build polarity into the series and test selectivity against related lipid-sensing GPCRs such as GPR40 and GPR120.
📄 Paper · bioRxiv ↗ Structure-based discovery of new GPR119 ligands from on-demand tera-scale chemical space