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

Tiago Rodrigues, Florian Sieglitz, Víctor J Somovilla, Pedro M S D Cal, Antony Galione, Francisco Corzana, Gonçalo J L Bernardes

Journal: Angewandte Chemie (International ed. in English) 2018;55(37):11077-81

PMID: 27391219

Free Full Text on PubMed Central View on PubMed

Abstract

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.

Address: Instituto de Medicina Molecular, Faculdade de Medicina da Universidade de Lisboa, Av. Prof. Egas Moniz, 1649-028, Lisboa, Portugal. [email protected].; Instituto de Medicina Molecular, Faculdade de Medicina da Universidade de Lisboa, Av. Prof. Egas Moniz, 1649-028, Lisboa, Portugal.; Departamento de Química, Centro de Investigación en Síntesis Química, Universidad de la Rioja, 26006, Logroño, Spain.; Department of Chemistry, University of Cambridge, Lensfield Road, CB2 1EW, Cambridge, UK.; Department of Pharmacology, University of Oxford, Mansfield Road, OX1 3QT, Oxford, UK.; Departamento de Química, Centro de Investigación en Síntesis Química, Universidad de la Rioja, 26006, Logroño, Spain. [email protected].; Instituto de Medicina Molecular, Faculdade de Medicina da Universidade de Lisboa, Av. Prof. Egas Moniz, 1649-028, Lisboa, Portugal. [email protected], [email protected].; Department of Chemistry, University of Cambridge, Lensfield Road, CB2 1EW, Cambridge, UK. [email protected], [email protected].

DOI: 10.1002/anie.201604336

Link outs

Free resources

Full Text Sources:

Other Literature Sources:

Miscellaneous:

https://assays.cancer.gov/CPTAC-177

Subscription / membership required

Full Text Sources:

https://doi.org/10.1002/anie.201604336

MeSH Terms: Calcium Channel Blockers, Calcium Channels, L-Type, Humans, Models, Molecular, Molecular Structure, Phyllanthus, Sesquiterpenes, Guaiane