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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. © 2015 Wiley Periodicals, Inc..

Registro:

Documento: Artículo
Título:Exploring the molecular basis of action of ring D aromatic steroidal antiestrogens
Autor:Alvarez, L.D.; Veleiro, A.S.; Burton, G.
Filiación:Departamento de Química Orgánica and UMYMFOR (CONICET-UBA), Facultad De Ciencias Exactas Y Naturales, Universidad De Buenos Aires, Buenos Aires, Argentina
Palabras clave:Antiestrogenic; Estrogen receptor; Molecular dynamics; Salpichrolide; Withanolide; antiestrogen; estradiol; estrogen receptor alpha; phytosterol; protein; protein his524; salpichrolide a; unclassified drug; ergosterol; estradiol; ligand; protein binding; salpichrolide A; selective estrogen receptor modulator; Article; breast cancer; cancer hormone therapy; conformational transition; controlled study; crystal structure; ligand binding; molecular dynamics; molecular model; priority journal; protein conformation; protein interaction; transcription initiation; analogs and derivatives; antagonists and inhibitors; binding site; chemistry; computer interface; human; molecular docking; molecular genetics; protein motif; protein secondary structure; protein tertiary structure; structure activity relation; synthesis; thermodynamics; Amino Acid Motifs; Binding Sites; Ergosterol; Estradiol; Estrogen Receptor alpha; Estrogen Receptor Modulators; Humans; Ligands; Molecular Docking Simulation; Molecular Dynamics Simulation; Molecular Sequence Data; Protein Binding; Protein Structure, Secondary; Protein Structure, Tertiary; Structure-Activity Relationship; Thermodynamics; User-Computer Interface
Año:2015
Volumen:83
Número:7
Página de inicio:1297
Página de fin:1306
DOI: http://dx.doi.org/10.1002/prot.24820
Título revista:Proteins: Structure, Function and Bioinformatics
Título revista abreviado:Proteins Struct. Funct. Bioinformatics
ISSN:08873585
CAS:estradiol, 50-28-2; protein, 67254-75-5; ergosterol, 23637-22-1, 2418-45-3, 3992-98-1, 57-87-4; Ergosterol; Estradiol; Estrogen Receptor alpha; Estrogen Receptor Modulators; Ligands; salpichrolide A
Registro:https://bibliotecadigital.exactas.uba.ar/collection/paper/document/paper_08873585_v83_n7_p1297_Alvarez

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Citas:

---------- APA ----------
Alvarez, L.D., Veleiro, A.S. & Burton, G. (2015) . Exploring the molecular basis of action of ring D aromatic steroidal antiestrogens. Proteins: Structure, Function and Bioinformatics, 83(7), 1297-1306.
http://dx.doi.org/10.1002/prot.24820
---------- CHICAGO ----------
Alvarez, L.D., Veleiro, A.S., Burton, G. "Exploring the molecular basis of action of ring D aromatic steroidal antiestrogens" . Proteins: Structure, Function and Bioinformatics 83, no. 7 (2015) : 1297-1306.
http://dx.doi.org/10.1002/prot.24820
---------- MLA ----------
Alvarez, L.D., Veleiro, A.S., Burton, G. "Exploring the molecular basis of action of ring D aromatic steroidal antiestrogens" . Proteins: Structure, Function and Bioinformatics, vol. 83, no. 7, 2015, pp. 1297-1306.
http://dx.doi.org/10.1002/prot.24820
---------- VANCOUVER ----------
Alvarez, L.D., Veleiro, A.S., Burton, G. Exploring the molecular basis of action of ring D aromatic steroidal antiestrogens. Proteins Struct. Funct. Bioinformatics. 2015;83(7):1297-1306.
http://dx.doi.org/10.1002/prot.24820