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

  1. Rodrigues, T. 4
  2. Sieglitz, F. 4
  3. Somovilla, V.J. 12
  4. Cal, P.M.S.D. 4
  5. Galione, A. 3
  6. Corzana, F. 1
  7. Bernardes, G.J.L. 24
  1. 1 Universidad de La Rioja
    info

    Universidad de La Rioja

    Logroño, España

    ROR https://ror.org/0553yr311

  2. 2 University of Cambridge
    info

    University of Cambridge

    Cambridge, Reino Unido

    ROR https://ror.org/013meh722

  3. 3 University of Oxford
    info

    University of Oxford

    Oxford, Reino Unido

    ROR https://ror.org/052gg0110

  4. 4 Universidade de Lisboa
    info

    Universidade de Lisboa

    Lisboa, Portugal

    ROR https://ror.org/01c27hj86

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Zeitschrift:
Angewandte Chemie International

ISSN: 1433-7851

Datum der Publikation: 2016

Ausgabe: 55

Nummer: 37

Seiten: 11077-11081

Art: Artikel

DOI: 10.1002/ANIE.201604336 SCOPUS: 2-s2.0-84990179056 WoS: WOS:000383642300018 GOOGLE SCHOLAR

Andere Publikationen in: Angewandte Chemie International

Institutionelles Repository: lock_openOpen Access Editor

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Diseño estructural de glicopeptidos de tipo mucina que incorporan miméticos del antigeno TN para desarrollar biomarcadores y vacunas contra el cáncer.

2016/00001/001

Zusammenfassung

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