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dc.contributor.author Alvarez, Lautaro Damian
dc.contributor.author Veleiro, Adriana Silvia
dc.contributor.author Burton, Gerardo
dc.date.available 2017-06-22T21:29:18Z
dc.date.issued 2015-07
dc.identifier.citation Alvarez, Lautaro Damian; Veleiro, Adriana Silvia; Burton, Gerardo; Exploring the molecular basis of action of ring D aromatic steroidal antiestrogens; Wiley; Proteins: Structure, Function And Genetics; 83; 7; 7-2015; 1297-1306
dc.identifier.issn 0887-3585
dc.identifier.uri http://hdl.handle.net/11336/18719
dc.description.abstract Salpichrolides are natural plant steroids that contain an unusual six-membered aromatic ring D. We recently reported that some of these compounds, and certain analogs with a simplified side chain, exhibited antagonist effects toward the human estrogen receptor (ER), a nuclear receptor whose endogenous ligand has an aromatic A ring (estradiol). Drugs acting through the inhibition or modulation of ERs are frequently used as a hormonal therapy for ER(+) breast cancer. Previous results suggested that the aromatic D ring was a key structural motif for the observed activity; thus, this modified steroid nucleus may provide a new scaffold for the design of novel antiestrogens. Using molecular dynamics (MD) simulation we have modeled the binding mode of the natural salpichrolide A and a synthetic analog with an aromatic D ring within the ERα. These results taken together with the calculated energetic contributions associated to the different ligand-binding modes are consistent with a preferred inverted orientation of the steroids in the ligand-binding pocket with the aromatic ring D occupying a position similar to that observed for the A ring of estradiol. Major changes in both dynamical behavior and global positioning of H11 caused by the loss of the ligand–His524 interaction might explain, at least in part, the molecular basis of the antagonism exhibited by these compounds. Using steered MD we also found a putative unbinding pathway for the steroidal ligands through a cavity formed by residues in H3, H7, and H11, which requires only minor changes in the overall receptor conformation.
dc.format application/pdf
dc.language.iso eng
dc.publisher Wiley
dc.rights info:eu-repo/semantics/restrictedAccess
dc.rights.uri https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
dc.subject ANTIESTROGEN
dc.subject SALPICHROLIDE
dc.subject ESTROGEN RECEPTOR
dc.subject MOLECULAR DYNAMICS
dc.subject.classification Química Orgánica
dc.subject.classification Ciencias Químicas
dc.subject.classification CIENCIAS NATURALES Y EXACTAS
dc.title Exploring the molecular basis of action of ring D aromatic steroidal antiestrogens
dc.type info:eu-repo/semantics/article
dc.type info:ar-repo/semantics/artículo
dc.type info:eu-repo/semantics/publishedVersion
dc.date.updated 2017-06-22T17:37:40Z
dc.journal.volume 83
dc.journal.number 7
dc.journal.pagination 1297-1306
dc.journal.pais Estados Unidos
dc.journal.ciudad Hoboken
dc.description.fil Fil: Alvarez, Lautaro Damian. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Unidad de Microanálisis y Métodos Físicos en Química Orgánica. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Unidad de Microanálisis y Métodos Físicos en Química Orgánica; Argentina
dc.description.fil Fil: Veleiro, Adriana Silvia. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Unidad de Microanálisis y Métodos Físicos en Química Orgánica. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Unidad de Microanálisis y Métodos Físicos en Química Orgánica; Argentina
dc.description.fil Fil: Burton, Gerardo. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Unidad de Microanálisis y Métodos Físicos en Química Orgánica. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Unidad de Microanálisis y Métodos Físicos en Química Orgánica; Argentina
dc.journal.title Proteins: Structure, Function And Genetics
dc.relation.alternativeid info:eu-repo/semantics/altIdentifier/doi/http://dx.doi.org/10.1002/prot.24820
dc.relation.alternativeid info:eu-repo/semantics/altIdentifier/url/http://onlinelibrary.wiley.com/doi/10.1002/prot.24820/abstract


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info:eu-repo/semantics/restrictedAccess Excepto donde se diga explícitamente, este item se publica bajo la siguiente descripción: Creative Commons Attribution-NonCommercial-ShareAlike 2.5 Unported (CC BY-NC-SA 2.5)