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

ALVAREZ, LAUTARO D.; VELEIRO, ADRIANA S.; BURTON, GERARDO

PROTEINS: STRUCTURE, FUNCTION AND GENETICS

WILEY-LISS, DIV JOHN WILEY & SONS INC

Año: 2015 vol. 83 p. 1297 - 1306

0887-3585

Salpichrolides are natural plant steroids that contain an unusual sixmembered aromatic ring D. We recently reported that some of these compounds, and certain analogues 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 simulation we have modelled the binding mode of the natural salpichrolide A and a synthetic analogue with an aromatic D ring within the ERá. 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 molecular dynamics we also found a putative unbinding pathway for the steroidal ligands through a cavity formed by residues in H3, H7 and H11, that requires only minor changes in the overall receptor conformation.