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Deorphaning the Macromolecular Targets of the Natural Anticancer Compound Doliculide
Gisbert Schneider1, Daniel Reker2, Tao Chen2
1Department of Chemistry and Applied Biosciences, Institute of Pharmaceutical Sciences, ETH Zürich, Wolfgang-Pauli-Strasse 10, 8093, Zürich, Switzerland. gisbert.schneider@pharma.ethz.ch.
Abstract:
The cyclodepsipeptide doliculide is a marine natural product with strong actin-polymerizing and anticancer activities. Evidence for doliculide acting as a potent and subtype-selective antagonist of prostanoid E receptor 3 (EP3) is presented. Computational target prediction suggested that this membrane receptor is a likely macromolecular target and enabled immediate in vitro validation. This proof-of-concept study demonstrates the in silico deorphanization of phenotypic screening hits as a viable concept for future natural-product-inspired chemical biology and drug discovery efforts.
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