Poul Nissen

Discovery of Tricyclic Clerodane Diterpenes as Sarco/Endoplasmic Reticulum Ca2+-ATPase Inhibitors and Structure-Activity Relationships

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaperJournal articleResearchpeer-review

  • Christian De Ford, University of Freiburg
  • ,
  • Carlos Calderón, University of Costa Rica
  • ,
  • Pankaj Sehgal, Centre for Membrane Pumps in Cells and Disease (PUMPkin), National Research Foundation
  • ,
  • Natalya U. Fedosova
  • Renato Murillo, University of Costa Rica
  • ,
  • Claus Olesen
  • Poul Nissen
  • Jesper V. Møller
  • Irmgard Merfort, University of Freiburg

Tricyclic clerodane diterpenes (TCDs) are natural compounds that often show potent cytotoxicity for cancer cells, but their mode of action remains elusive. A computationally based similarity search (CDRUG), combined with principal component analysis (ChemGPS-NP) and docking calculations (GOLD 5.2), suggested TCDs to be inhibitors of the sarco/endoplasmic reticulum Ca2+-ATPase (SERCA) pump, which is also the target of the sesquiterpene lactone thapsigargin. Biochemical studies were performed with 11 TCDs on purified rabbit skeletal muscle sarcoplasmic reticulum membranes, which are highly enriched with the SERCA1a isoform. Casearborin D (2) exhibited the highest affinity, with a KD value of 2 μM and giving rise to complete inhibition of SERCA1a activity. Structure-activity relationships revealed that functionalization of two acyl side chains (R1 and R4) and the hydrophobicity imparted by the aliphatic chain at C-9, as well as a C-3,C-4 double bond, play crucial roles for inhibitory activity. Docking studies also suggested that hydrophobic interactions in the binding site, especially with Phe256 and Phe834, may be important for a strong inhibitory activity of the TCDs. In conclusion, a novel class of SERCA inhibitory compounds is presented.

Original languageEnglish
JournalJournal of Natural Products
Volume78
Issue6
Pages (from-to)1262-1270
Number of pages9
ISSN0163-3864
DOIs
Publication statusPublished - 26 Jun 2015

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