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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Detalles Bibliográficos
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
Descripción
Sumario: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..

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