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Highlights • A target fishing protocol was developed to define activity of orphan food compounds. • The fungal secondary metabolite atromentin served for the proof of concept. • A combined in silico/in vitro approach succeeded in activity identification. • Estrogen receptors and 17-β-HSDs were identified as relevant biological targets. • Mild estrogenicity of atromentin was experimentally confirmed. Abstract Many small molecules of food origin may effect human health but lack an adequate description of their biological activity. To fill this knowledge gap, a first-line workflow is needed to assign putative functions, rank the endpoints for testing and guide wet-lab experiments. In this framework, the identification of potential biological targets can be used to probe the activity of orphan compounds using a so-called “target fishing” approach. Here, we present a proof of concept study using an in silico/in vitro target fishing approach on the fungal secondary metabolite atromentin. The procedure relies on a computational screening for activity identification coupled with experimental trials for dose-response characterization. Computational results identified estrogen receptors and 17-β-hydroxysteroid dehydrogenase as potential targets. Experiments confirmed a weak estrogenic activity, supporting the reliability of the procedure. Despite limited estrogenicity of atromentin, the proposed inhibition of 17-β-hydroxysteroid dehydrogenase should be considered as a source for endocrine disruptive effects. [ABSTRACT FROM AUTHOR]