Unveiling (-)-EnglerinA as a Modulator of L-Type Calcium Channels

The voltage-dependent L-type Ca2+channel was identified as a macromolecular target for (-)-englerinA. This finding was reached by using an unprecedented ligand-based prediction platform and the natural product piperlongumine as a pharmacophore probe. (-)-EnglerinA features high substructure dissimil...

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Published inAngewandte Chemie International Edition Vol. 55; no. 37; p. 11077
Main Authors Rodrigues, Tiago, Sieglitz, Florian, Somovilla, Víctor J, Cal, Pedro M S D, Galione, Antony, Corzana, Francisco, Bernardes, Gonçalo J L
Format Journal Article
LanguageEnglish
Published Weinheim Wiley Subscription Services, Inc 05.09.2016
EditionInternational ed. in English
Subjects
Calcium
Natural products
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Summary:The voltage-dependent L-type Ca2+channel was identified as a macromolecular target for (-)-englerinA. This finding was reached by using an unprecedented ligand-based prediction platform and the natural product piperlongumine as a pharmacophore probe. (-)-EnglerinA features high substructure dissimilarity to known ligands for voltage-dependent Ca2+ 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.
ISSN:1433-7851
1521-3773
DOI:10.1002/anie.201604336