Exploring the molecular basis of action of ring D aromatic steroidal antiestrogens

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 endogeno...

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Autores principales:	Alvarez, L.D., Veleiro, A.S., Burton, G.
Formato:	JOUR
Materias:	Antiestrogenic Estrogen receptor Molecular dynamics Salpichrolide Withanolide antiestrogen estradiol estrogen receptor alpha phytosterol protein protein his524 salpichrolide a unclassified drug ergosterol 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
Acceso en línea:	http://hdl.handle.net/20.500.12110/paper_08873585_v83_n7_p1297_Alvarez
Aporte de:	Biblioteca Digital - Facultad de Ciencias Exactas y Naturales (UBA) de Universidad de Buenos Aires

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spelling	todo:paper_08873585_v83_n7_p1297_Alvarez2023-10-03T15:40:54Z Exploring the molecular basis of action of ring D aromatic steroidal antiestrogens Alvarez, L.D. Veleiro, A.S. Burton, G. 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 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.. Fil:Veleiro, A.S. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina. Fil:Burton, G. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina. JOUR info:eu-repo/semantics/openAccess http://creativecommons.org/licenses/by/2.5/ar http://hdl.handle.net/20.500.12110/paper_08873585_v83_n7_p1297_Alvarez
institution	Universidad de Buenos Aires
institution_str	I-28
repository_str	R-134
collection	Biblioteca Digital - Facultad de Ciencias Exactas y Naturales (UBA)
topic	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
spellingShingle	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 Alvarez, L.D. Veleiro, A.S. Burton, G. Exploring the molecular basis of action of ring D aromatic steroidal antiestrogens
topic_facet	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
description	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..
format	JOUR
author	Alvarez, L.D. Veleiro, A.S. Burton, G.
author_facet	Alvarez, L.D. Veleiro, A.S. Burton, G.
author_sort	Alvarez, L.D.
title	Exploring the molecular basis of action of ring D aromatic steroidal antiestrogens
title_short	Exploring the molecular basis of action of ring D aromatic steroidal antiestrogens
title_full	Exploring the molecular basis of action of ring D aromatic steroidal antiestrogens
title_fullStr	Exploring the molecular basis of action of ring D aromatic steroidal antiestrogens
title_full_unstemmed	Exploring the molecular basis of action of ring D aromatic steroidal antiestrogens
title_sort	exploring the molecular basis of action of ring d aromatic steroidal antiestrogens
url	http://hdl.handle.net/20.500.12110/paper_08873585_v83_n7_p1297_Alvarez
work_keys_str_mv	AT alvarezld exploringthemolecularbasisofactionofringdaromaticsteroidalantiestrogens AT veleiroas exploringthemolecularbasisofactionofringdaromaticsteroidalantiestrogens AT burtong exploringthemolecularbasisofactionofringdaromaticsteroidalantiestrogens
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Exploring the molecular basis of action of ring D aromatic steroidal antiestrogens

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