Deorphaning the Macromolecular Targets of the Natural Anticancer Compound Doliculide

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 membra...

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Bibliographic Details
Published in:Angewandte Chemie International Edition 2016-09, Vol.55 (40), p.12408-12411
Main Authors: Schneider, Gisbert, Reker, Daniel, Chen, Tao, Hauenstein, Kurt, Schneider, Petra, Altmann, Karl-Heinz
Format: Article
Language:English
Subjects:
Actin
anticancer compounds
Anticancer properties
Biological Products - chemistry
Biological Products - metabolism
Cancer
cheminformatics
Computer applications
Depsipeptides - chemical synthesis
Depsipeptides - chemistry
Depsipeptides - metabolism
Drug Design
Drug discovery
HEK293 Cells
Humans
Kinetics
Ligands
Macromolecules
natural products
Pharmaceutical industry
Polymerization
polypharmacology
Receptors, Prostaglandin E, EP3 Subtype - antagonists & inhibitors
Receptors, Prostaglandin E, EP3 Subtype - genetics
Receptors, Prostaglandin E, EP3 Subtype - metabolism
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Summary: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. Computational adoption services: Macromolecular targets of the marine natural product doliculide were successfully identified using a chemocentric computer‐based prediction method. This study reveals this cyclodepsipeptide as a potent antagonist of the human prostanoid receptor EP3.
ISSN:1433-7851
1521-3773
DOI:10.1002/anie.201605707