Unveiling (−)-Englerin A as a Modulator of L-Type Calcium Channels
- Rodrigues, T. 4
- Sieglitz, F. 4
- Somovilla, V.J. 12
- Cal, P.M.S.D. 4
- Galione, A. 3
- Corzana, F. 1
- Bernardes, G.J.L. 24
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1
Universidad de La Rioja
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2
University of Cambridge
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3
University of Oxford
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4
Universidade de Lisboa
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ISSN: 1433-7851
Año de publicación: 2016
Volumen: 55
Número: 37
Páginas: 11077-11081
Tipo: Artículo
beta Ver similares en nube de resultadosOtras publicaciones en: Angewandte Chemie International
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Resumen
The voltage-dependent L-type Ca2+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 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. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim