title: Unveiling (-)-Englerin A as a Modulator of L-Type Calcium Channels.
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.
authors.affiliation: Instituto de Medicina Molecular, Faculdade de Medicina da Universidade de Lisboa, Av. Prof. Egas Moniz, 1649-028, Lisboa, Portugal. tiago.rodrigues@medicina.ulisboa.pt.
authors.forename: Tiago
authors.initials: T
authors.lastname: Rodrigues
authors.affiliation: Instituto de Medicina Molecular, Faculdade de Medicina da Universidade de Lisboa, Av. Prof. Egas Moniz, 1649-028, Lisboa, Portugal.
authors.forename: Florian
authors.initials: F
authors.lastname: Sieglitz
authors.affiliation: 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.
authors.forename: Víctor J
authors.initials: VJ
authors.lastname: Somovilla
authors.affiliation: Instituto de Medicina Molecular, Faculdade de Medicina da Universidade de Lisboa, Av. Prof. Egas Moniz, 1649-028, Lisboa, Portugal.
authors.forename: Pedro M S D
authors.initials: PM
authors.lastname: Cal
authors.affiliation: Department of Pharmacology, University of Oxford, Mansfield Road, OX1 3QT, Oxford, UK.
authors.forename: Antony
authors.initials: A
authors.lastname: Galione
authors.affiliation: Departamento de Química, Centro de Investigación en Síntesis Química, Universidad de la Rioja, 26006, Logroño, Spain. francisco.corzana@unirioja.es.
authors.forename: Francisco
authors.initials: F
authors.lastname: Corzana
authors.affiliation: Instituto de Medicina Molecular, Faculdade de Medicina da Universidade de Lisboa, Av. Prof. Egas Moniz, 1649-028, Lisboa, Portugal. gbernardes@medicina.ulisboa.pt, gb453@cam.ac.uk.|Department of Chemistry, University of Cambridge, Lensfield Road, CB2 1EW, Cambridge, UK. gbernardes@medicina.ulisboa.pt, gb453@cam.ac.uk.
authors.forename: Gonçalo J L
authors.identifier: 0000-0001-6594-8917
authors.initials: GJ
authors.lastname: Bernardes
mesh_terms: D002121:Calcium Channel Blockers / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D020746:Calcium Channels, L-Type / Q000378:metabolism*; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D029803:Phyllanthus / Q000737:chemistry; D045789:Sesquiterpenes, Guaiane / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*
chemical_list: D002121:Calcium Channel Blockers; D020746:Calcium Channels, L-Type; D045789:Sesquiterpenes, Guaiane; C534971:englerin A
keywords: chemical biology; molecular recognition; natural products; target prediction; voltage-gated calcium channels