Revealing the macromolecular targets of complex natural products

Nat Chem. 2014 Dec;6(12):1072-8. doi: 10.1038/nchem.2095. Epub 2014 Nov 2.


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'.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Arachidonic Acid / chemistry
  • Biological Products / chemistry*
  • Drug Design
  • Drug Discovery / methods*
  • Macrolides / chemistry
  • Macromolecular Substances / chemistry*
  • Molecular Structure
  • Receptors, Cytoplasmic and Nuclear / physiology
  • Thiazoles / chemistry
  • Vacuolar Proton-Translocating ATPases / antagonists & inhibitors


  • Biological Products
  • Macrolides
  • Macromolecular Substances
  • Receptors, Cytoplasmic and Nuclear
  • Thiazoles
  • archazolid A
  • farnesoid X-activated receptor
  • Arachidonic Acid
  • Vacuolar Proton-Translocating ATPases