Structure-based discovery of new GPR119 ligands from on-demand tera-scale chemical space

The orphan G protein-coupled receptor GPR119 is involved in glucose homeostasis and is considered a promising target for the treatment of diabetes and other metabolic diseases. The recently solved structures of GPR119 in complex with potential endogenous lipid agonists, including oleoylethanolamide (OEA), provide a solid platform for 3D pharmacology analysis and structure-based ligand discovery. Here, we employed the V-SYNTHES2 approach to screen ~3 trillion on-demand compounds from Enamine xREAL chemical space to identify several new chemotypes of GPR119 agonists and antagonists. Structure-guided analog-by-catalog hit expansion of new chemotypes and stereoselective synthesis resulted in a series of full and partial agonists with low-micromolar potencies in functional assays. Cryo-EM structures of active GPR119-Gs complexes bound to three of the hits validated the docking predictions and established further SAR insights into ligand-receptor interactions, enabling the discovery of BRI-17403 and BRI-17409 agonists with EC50 values of 1.6 μM and 1.3 μM, respectively. These results demonstrate the utility of structure-based screening of tera-scale on-demand chemical spaces in accelerating drug discovery for therapeutically relevant orphan GPCRs.