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

Abstract

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.

Complexity‐to‐Diversity and Pseudo‐Natural Product Strategies as Powerful Platforms for Deciphering Next‐Generation Therapeutics

“…[48][49]63,108,[112][113] Biological activities of pseudo-NPs are usually assessed using "unbiased assays", that involve screening against biological systems instead of monitoring a single target in a phenotypic screen. [49,64,108,110,114] For example, phenotypic screening of pseudo-NP identified first-in-class chemical probes such as the chromopyrones 105 that possesses a dual inhibition of glucose transporters GLUT-1/3 as well as exhibiting anticancer activity by inhibiting cancer cells growth. [115] Additionally, the pseudo-NP myokinasib (106) inhibits myosin light chain kinase ChemMedChem 1 (MLCK1), whereas the pseudo-NP indocinchonia 107 inhibits autophagy (Figure 8b).…”