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

Cryo-EM validated structure-guided screening of GPR119 identified new agonists, including BRI-17403 and BRI-17409, with EC50 values of 1.6 M and 1.3 M.

• Why it matters: GPR119 is an orphan GPCR linked to glucose homeostasis, but ligand discovery has been limited; new structure-based methods are needed to expand chemotypes for metabolic disease targets.
• What they did: Using V-SYNTHES2, the team screened ~3 trillion on-demand Enamine xREAL compounds, then expanded hits by catalog analogs and synthesized stereoselective analogs for functional assays.
• The result: Active GPR119-Gs Cryo-EM structures bound to three hits supported docking predictions and refined SAR, enabling identification of BRI-17403 and BRI-17409 agonists.

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