Revealing the macromolecular targets of complex natural products.

Journal Article (Journal Article)

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'.

Full Text

Duke Authors

Cited Authors

  • Reker, D; Perna, AM; Rodrigues, T; Schneider, P; Reutlinger, M; Mönch, B; Koeberle, A; Lamers, C; Gabler, M; Steinmetz, H; Müller, R; Schubert-Zsilavecz, M; Werz, O; Schneider, G

Published Date

  • December 2014

Published In

Volume / Issue

  • 6 / 12

Start / End Page

  • 1072 - 1078

PubMed ID

  • 25411885

Electronic International Standard Serial Number (EISSN)

  • 1755-4349

International Standard Serial Number (ISSN)

  • 1755-4330

Digital Object Identifier (DOI)

  • 10.1038/nchem.2095


  • eng