Finally, using an inducible ROR reporter system, we showed that 11-HSD1 and 11-HSD2 controlled ROR activity. These findings revealed a novel glucocorticoidindependent prereceptor regulation mechanism by 11-HSDs that warrants further investigation.

Natural products comprise a rich reservoir for innovative drug leads and are a constant source of bioactive compounds. To find pharmacological targets for new or already known natural products using modern computer-aided methods is a current endeavor in drug discovery. Nature’s treasures, however, could be used more effectively. Yet, reliable pipelines for the large-scale target prediction of natural products are still rare. We developed an in silico workflow consisting of four independent, stand-alone target prediction tools and evaluated its performance on dihydrochalcones (DHCs)—a well-known class of natural products. Thereby, we revealed four previously unreported protein targets for DHCs, namely 5-lipoxygenase, cyclooxygenase-1, 17β-hydroxysteroid dehydrogenase 3, and aldo-keto reductase 1C3. Moreover, we provide a thorough strategy on how to perform computational target predictions and guidance on using the respective tools.

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Highlights  TBT and TPT induce the transcription of 11β-HSD2 in JEG-3 cells  Upregulation of 11β-HSD2 results in reduced cortisol-dependent activation of the GR  RXRα is involved in the TBT and TPT induced effect on 11β-HSD2  Fludioxonil and chlorotriphenylsilane activate RXRα and induce 11β-HSD2 expression

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