Repository logo

Unveiling (-)-Englerin A as a Modulator of L-Type Calcium Channels.

Accepted version

Change log


Rodrigues, Tiago 
Sieglitz, Florian 
Somovilla, Víctor J 
Cal, Pedro MSD 
Galione, Antony 


The voltage-dependent L-type Ca(2+) channel was identified as a macromolecular target for (-)-englerin A. This finding was reached by using an unprecedented ligand-based prediction platform and the natural product piperlongumine as a pharmacophore probe. (-)-Englerin A features high substructure dissimilarity to known ligands for voltage-dependent Ca(2+) channels, selective binding affinity for the dihydropyridine site, and potent modulation of calcium signaling in muscle cells and vascular tissue. The observed activity was rationalized at the atomic level by molecular dynamics simulations. Experimental confirmation of this hitherto unknown macromolecular target expands the bioactivity space for this natural product and corroborates the effectiveness of chemocentric computational methods for prioritizing target-based screens and identifying binding counterparts of complex natural products.



chemical biology, molecular recognition, natural products, target prediction, voltage-gated calcium channels, Calcium Channel Blockers, Calcium Channels, L-Type, Humans, Models, Molecular, Molecular Structure, Phyllanthus, Sesquiterpenes, Guaiane

Journal Title

Angew Chem Int Ed Engl

Conference Name

Journal ISSN


Volume Title



Engineering and Physical Sciences Research Council (EP/M003647/1)
European Commission (EC) (852985)
We thank FCT Portugal (FCT Investigator to G.J.L.B. and Postdoctoral Fellowship to P.M.S.D.C.), the European Commission (Marie-Curie CIG to G.J.L.B.), DFG (SI 2117/1-1 to F.S.), the EPSRC and MRC for financial support.