Journal: Nature Communications

Article Title: Ultra-large virtual screening unveils potent agonists of the neuromodulatory orphan receptor GPR139

doi: 10.1038/s41467-025-66845-y

Figure Lengend Snippet: a A structure of the active GPR139 bound to the reference compound JNJ-63533054 was used in the ultra-large docking screen. b A library of 235 million lead-like compounds from the ZINC database was docked to the orthosteric site using DOCK3.7, and a set of 68 top-ranked compounds were selected for synthesis. c Primary screening of compounds at 10 µM in Ca 2+ mobilization assay. A threshold of 25% Ca 2+ response was used to select compounds for further evaluation. Data represent mean ± SEM of at least three independent experiments performed in triplicates and are normalized to buffer (0%) and 10 µM of the control ( Lundbeck Cmp 1a , 100%).

Article Snippet: Notably, the EC 50 values of the most potent compounds ( and , EC 50 = 160 and 320 nM, respectively) were comparable to the reference compound Lundbeck Cmp 1a (EC 50 = 200 nM).

Techniques: Control

Journal: Nature Communications

Article Title: Ultra-large virtual screening unveils potent agonists of the neuromodulatory orphan receptor GPR139

doi: 10.1038/s41467-025-66845-y

Figure Lengend Snippet: a Compounds – 5 were pharmacologically characterized for their ability to b stimulate intracellular Ca 2+ mobilization and c inositol monophosphate (IP ) accumulation. Data represent mean ± SEM of at least three independent experiments performed in triplicates and are normalized to buffer (0%) and 10 µM of the control ( Lundbeck Cmp 1a , 100%). The potencies (EC 50 ) determined using the Ca 2+ mobilization assay are shown below each compound structure in ( a ). d Predicted binding modes of compounds – 5 . The receptor is depicted as a cartoon with ligands and selected side chains shown in sticks. Hydrogen bonds are indicated using dashed lines. The structures of the predicted complexes are provided in Supplementary Data .

Article Snippet: Notably, the EC 50 values of the most potent compounds ( and , EC 50 = 160 and 320 nM, respectively) were comparable to the reference compound Lundbeck Cmp 1a (EC 50 = 200 nM).

Techniques: Control, Binding Assay

Journal: Nature Communications

Article Title: Ultra-large virtual screening unveils potent agonists of the neuromodulatory orphan receptor GPR139

doi: 10.1038/s41467-025-66845-y

Figure Lengend Snippet: a , b Structure of core scaffold (R = aromatic ring) explored in optimization and representative analogs of compound 1 with EC 50 values from the Ca 2+ mobilization assay. The blue and green areas in ( a ) show analogs based on six-membered and five-membered ring substituents, respectively. c The reference GPR139 agonists Lundbeck Cmp 1a, JNJ-63533054, TAK-041 , and compound 1.1 were evaluated for their ability to stimulate intracellular Ca 2+ mobilization and IP 1 accumulation. Data represent mean ± SEM of at least three independent experiments performed in triplicates and are normalized to buffer (0%) and 10 µM of the control ( Lundbeck Cmp 1a , 100%). d Chemical structures comparison of the reference agonists and compound 1.1 .

Article Snippet: Notably, the EC 50 values of the most potent compounds ( and , EC 50 = 160 and 320 nM, respectively) were comparable to the reference compound Lundbeck Cmp 1a (EC 50 = 200 nM).

Techniques: Control, Comparison