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Natural Products (NP) are a major source of inspiration to develop novel bioactive substances. Various strategies were developed to make use of the relevance of NPs in drug design strategies. It has been shown that NP-derived fragments may still be of biological relevance. Thus, combining various different NP-derived fragments may result in new biologically relevant molecules. These compounds retain some physicochemical properties of NPs but are not accessible through biosynthesis and were therefore termed pseudo-NPs. Since it is not possible to infer the bioactivity of pseudo-NPs from their NP-derived fragments, it is not straightforward to identify their potential targets. Hence more general, morphological phenotypic screens may be the best methods to identify impacted pathways. We highlight the potential of the pseudo-NP approach combined with a recent morphological-, image-based screening technology termed Cell Painting.

Identifying bioactivity of pseudo-natural products using the Cell Painting assay