Revealing the macromolecular targets of complex natural products

Reker, Daniel and Perna, Anna M. and Rodrigues, Tiago and Schneider, Petra and Reutlinger, Michael and Mönch, Bettina and Koeberle, Andreas and Lamers, Christina and Gabler, Matthias and Steinmetz, Heinrich and Müller, Rolf and Schubert-Zsilavecz, Manfred and Werz, Oliver and Schneider, Gisbert. (2014) Revealing the macromolecular targets of complex natural products. Nature Chemistry, 6 (12). pp. 1072-1078.

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Official URL: https://edoc.unibas.ch/70325/

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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'.
Faculties and Departments:05 Faculty of Science > Departement Pharmazeutische Wissenschaften > Pharmazie > Molekulare Pharmazie (Ricklin)
UniBasel Contributors:Lamers, Christina
Item Type:Article, refereed
Article Subtype:Research Article
Note:Publication type according to Uni Basel Research Database: Journal article
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Last Modified:16 Nov 2020 10:34
Deposited On:16 Nov 2020 10:34

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