title: Revealing the macromolecular targets of complex natural products.
abstract: Natural products have long been a source of useful biological activity for the development of new drugs. Their macromolecular targets are, however, largely unknown, which hampers rational drug design and optimization. Here we present the development and experimental validation of a computational method for the discovery of such targets. The technique does not require three-dimensional target models and may be applied to structurally complex natural products. The algorithm dissects the natural products into fragments and infers potential pharmacological targets by comparing the fragments to synthetic reference drugs with known targets. We demonstrate that this approach results in confident predictions. In a prospective validation, we show that fragments of the potent antitumour agent archazolid A, a macrolide from the myxobacterium Archangium gephyra, contain relevant information regarding its polypharmacology. Biochemical and biophysical evaluation confirmed the predictions. The results obtained corroborate the practical applicability of the computational approach to natural product 'de-orphaning'.
authors.affiliation: Swiss Federal Institute of Technology (ETH), Department of Chemistry and Applied Biosciences, Institute of Pharmaceutical Sciences, Vladimir-Prelog-Weg 4, 8093 Zürich, Switzerland.
authors.forename: Daniel
authors.initials: D
authors.lastname: Reker
authors.affiliation: Swiss Federal Institute of Technology (ETH), Department of Chemistry and Applied Biosciences, Institute of Pharmaceutical Sciences, Vladimir-Prelog-Weg 4, 8093 Zürich, Switzerland.
authors.forename: Anna M
authors.initials: AM
authors.lastname: Perna
authors.affiliation: Swiss Federal Institute of Technology (ETH), Department of Chemistry and Applied Biosciences, Institute of Pharmaceutical Sciences, Vladimir-Prelog-Weg 4, 8093 Zürich, Switzerland.
authors.forename: Tiago
authors.initials: T
authors.lastname: Rodrigues
authors.affiliation: Swiss Federal Institute of Technology (ETH), Department of Chemistry and Applied Biosciences, Institute of Pharmaceutical Sciences, Vladimir-Prelog-Weg 4, 8093 Zürich, Switzerland.
authors.forename: Petra
authors.initials: P
authors.lastname: Schneider
authors.affiliation: Swiss Federal Institute of Technology (ETH), Department of Chemistry and Applied Biosciences, Institute of Pharmaceutical Sciences, Vladimir-Prelog-Weg 4, 8093 Zürich, Switzerland.
authors.forename: Michael
authors.initials: M
authors.lastname: Reutlinger
authors.affiliation: Friedrich-Schiller-Universität Jena, Institut für Pharmazie, Philosophenweg 14, 07743 Jena, Germany.
authors.forename: Bettina
authors.initials: B
authors.lastname: Mönch
authors.affiliation: Friedrich-Schiller-Universität Jena, Institut für Pharmazie, Philosophenweg 14, 07743 Jena, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Koeberle
authors.affiliation: Goethe-Universität, Institut für Pharmazeutische Chemie, Max-von-Laue-Str. 9, 60438 Frankfurt a. M., Germany.
authors.forename: Christina
authors.initials: C
authors.lastname: Lamers
authors.affiliation: Goethe-Universität, Institut für Pharmazeutische Chemie, Max-von-Laue-Str. 9, 60438 Frankfurt a. M., Germany.
authors.forename: Matthias
authors.identifier: 0000000175484124
authors.initials: M
authors.lastname: Gabler
authors.affiliation: Helmholtz Institut für Pharmazeutische Forschung, Helmholtz Zentrum für Infektionsforschung und Pharmazeutische Biotechnologie, Universität des Saarlandes, 66041 Saarbrücken, Germany.
authors.forename: Heinrich
authors.initials: H
authors.lastname: Steinmetz
authors.affiliation: Helmholtz Institut für Pharmazeutische Forschung, Helmholtz Zentrum für Infektionsforschung und Pharmazeutische Biotechnologie, Universität des Saarlandes, 66041 Saarbrücken, Germany.
authors.forename: Rolf
authors.initials: R
authors.lastname: Müller
authors.affiliation: Goethe-Universität, Institut für Pharmazeutische Chemie, Max-von-Laue-Str. 9, 60438 Frankfurt a. M., Germany.
authors.forename: Manfred
authors.initials: M
authors.lastname: Schubert-Zsilavecz
authors.affiliation: Friedrich-Schiller-Universität Jena, Institut für Pharmazie, Philosophenweg 14, 07743 Jena, Germany.
authors.forename: Oliver
authors.initials: O
authors.lastname: Werz
authors.affiliation: Swiss Federal Institute of Technology (ETH), Department of Chemistry and Applied Biosciences, Institute of Pharmaceutical Sciences, Vladimir-Prelog-Weg 4, 8093 Zürich, Switzerland.
authors.forename: Gisbert
authors.initials: G
authors.lastname: Schneider
mesh_terms: D016718:Arachidonic Acid / Q000737:chemistry; D001688:Biological Products / Q000737:chemistry*; D015195:Drug Design; D055808:Drug Discovery / Q000379:methods*; D018942:Macrolides / Q000737:chemistry; D046911:Macromolecular Substances / Q000737:chemistry*; D015394:Molecular Structure; D018160:Receptors, Cytoplasmic and Nuclear / Q000502:physiology; D013844:Thiazoles / Q000737:chemistry; D025262:Vacuolar Proton-Translocating ATPases / Q000037:antagonists & inhibitors; D000099150:Receptor, Farnesoid X-Activated
chemical_list: D016718:Arachidonic Acid; D001688:Biological Products; D018942:Macrolides; D046911:Macromolecular Substances; D018160:Receptors, Cytoplasmic and Nuclear; D013844:Thiazoles; D025262:Vacuolar Proton-Translocating ATPases; D000099150:Receptor, Farnesoid X-Activated; C519727:archazolid A