In a single concentration functional assay, 15 out of 123 NGT compounds showed more than 50% inhibition at 30 µM concentration, compared to 11 out of 129 HE compounds (Supporting Information) . This corresponds to a 43% higher hit rate for NGT (12.2%) than for HE (8.5%, p = 0.23, one-sided). Moreover, AtomNet scores do not differentiate between antagonists and agonists; NGT identified three additional compounds that showed more than 50% activation compared to one with HE, resulting in a 57% higher combined hit rate for NGT (14.6%) than for HE (9.3%, p = 0.13 one-sided). These findings confirm a notable hit rate advantage for NGT to generate starting points from vast chemical universes. Next, we selected compounds for a subsequent dose-response relationship assay. We calculated lipophilic ligand efficiency (cLLE) from single concentration-estimated pIC50 and cLogD, and selected compounds with cLLE > 1.9 or estimated pIC50 > 4.9. This resulted in 5 compounds for each method. All selected antagonists validated in the concentration response assay (Fig 4C, Table ). The most potent NGT compound reported an EC50 = 6.7 µM corresponding to a Ligand Efficiency (LE) of 0.26 (Fig 4D ). One HE compound was slightly more potent (EC50 = 4.1 µM) at slightly worse LE = 0.22 (Fig 4D ). We also selected the two strongest agonists for each method. Surprisingly, we found that both agonists were inactive in dose-response.