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 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.
Departamento de Química Orgánica and UMYMFOR (CONICET-UBA), Facultad De Ciencias Exactas Y Naturales, Universidad De Buenos Aires, Buenos Aires, Argentina.
Lautaro D
LD
Alvarez
Departamento de Química Orgánica and UMYMFOR (CONICET-UBA), Facultad De Ciencias Exactas Y Naturales, Universidad De Buenos Aires, Buenos Aires, Argentina.
Adriana S
AS
Veleiro
Departamento de Química Orgánica and UMYMFOR (CONICET-UBA), Facultad De Ciencias Exactas Y Naturales, Universidad De Buenos Aires, Buenos Aires, Argentina.
Gerardo
G
Burton
D020816:Amino Acid Motifs; D001665:Binding Sites; D004875:Ergosterol / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry; D004958:Estradiol / Q000737:chemistry*; D020847:Estrogen Receptor Modulators / Q000138:chemical synthesis / Q000737:chemistry*; D047628:Estrogen Receptor alpha / Q000037:antagonists & inhibitors* / Q000737:chemistry; D006801:Humans; D008024:Ligands; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D008969:Molecular Sequence Data; D011485:Protein Binding; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D013329:Structure-Activity Relationship; D013816:Thermodynamics; D014584:User-Computer Interface
D020847:Estrogen Receptor Modulators; D047628:Estrogen Receptor alpha; D008024:Ligands; C453519:salpichrolide A; D004958:Estradiol; D004875:Ergosterol
antiestrogenic; estrogen receptor; molecular dynamics; salpichrolide; withanolide