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 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.
Department of Chemistry and Applied Biosciences, Institute of Pharmaceutical Sciences, ETH Zürich, Wolfgang-Pauli-Strasse 10, 8093, Zürich, Switzerland. gisbert.schneider@pharma.ethz.ch.
Gisbert
G
Schneider
Department of Chemistry and Applied Biosciences, Institute of Pharmaceutical Sciences, ETH Zürich, Wolfgang-Pauli-Strasse 10, 8093, Zürich, Switzerland.
Daniel
D
Reker
Department of Chemistry and Applied Biosciences, Institute of Pharmaceutical Sciences, ETH Zürich, Wolfgang-Pauli-Strasse 10, 8093, Zürich, Switzerland.
Tao
T
Chen
Department of Chemistry and Applied Biosciences, Institute of Pharmaceutical Sciences, ETH Zürich, Wolfgang-Pauli-Strasse 10, 8093, Zürich, Switzerland.
Kurt
K
Hauenstein
Department of Chemistry and Applied Biosciences, Institute of Pharmaceutical Sciences, ETH Zürich, Wolfgang-Pauli-Strasse 10, 8093, Zürich, Switzerland.|inSili.com LLC, Zürich, Switzerland.
Petra
P
Schneider
Department of Chemistry and Applied Biosciences, Institute of Pharmaceutical Sciences, ETH Zürich, Wolfgang-Pauli-Strasse 10, 8093, Zürich, Switzerland.
Karl-Heinz
KH
Altmann
D001688:Biological Products / Q000737:chemistry / Q000378:metabolism*; D047630:Depsipeptides / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism*; D015195:Drug Design; D057809:HEK293 Cells; D006801:Humans; D007700:Kinetics; D008024:Ligands; D058308:Receptors, Prostaglandin E, EP3 Subtype / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism
D001688:Biological Products; D047630:Depsipeptides; D008024:Ligands; D058308:Receptors, Prostaglandin E, EP3 Subtype; C424144:doliculide
anticancer compounds; cheminformatics; drug discovery; natural products; polypharmacology