The selected 14 compounds were prepared in-batch (Supporting Scheme S1), purified, and fully characterized on LXRα and LXRβ (Table ). Of these compounds, only compounds 2 and 3 were not confirmed to be active in the follow-up screening, suggesting that some other components in the crude reaction product mixture had activated LXRs in the primary screening. This finding indicates that the hexafluoro-2-phenyl-isopropanoyl moiety is not sufficient for LXR activation, despite its ubiquity among de novo designs. The potencies of the remaining 12 LXR modulators were in the range of EC50 = 0.18 -4.5 µM for LXRα and EC50 = 0.34 -4.0 µM for LXRβ. In agreement with the primary screening data, compound 6 displayed the highest potency on LXRα, with an EC50 of 0.183 ± 0.006 µM and 32-fold maximum activation. Compound 15 was confirmed as the most potent LXRβ agonist, with an EC50 of 0.34 ± 0.02 µM and 38-fold maximum receptor activation. ). Furthermore, the scaffolds of compounds 1 and 13 were not present in any of the 15,247 molecules annotated in the Nuclear Receptor Activity (NURA) dataset. Compound 15, the most potent LXRβ agonist, had the lowest fragment similarity to the fine-tuning molecules, as captured by Tanimoto similarity on Morgan molecular fingerprints (Supporting Table ). These results corroborate the capacity of the computational pipeline to explore narrow regions of the chemical space defined by the known LXR agonists, while at the same time providing hitherto unexplored molecular cores for further compound optimization.