10β-Hydroxyestra-1,4-diene-3,17-dione Does Not Bind to the Nuclear Estrogen Receptor α

Abstract

The lack of nuclear estrogen receptor (ER and ER{beta}) bindings of 10{beta}-hydroxyestra-1,4-diene-3,17-dione (HEDD) and structurally related steroidal para-quinols have been shown by an extensive series of multidisciplinary investigational evidence including specific receptor binding studies. In support of the latter, the absence of estrogen-derived para-quinols in vivo uterotrophic effects has also been well documented. Via in silico docking, a recent publication by Canario et al. (2022) reported a robust binding of HEDD (Figure 1B) to ER. The authors claimed a strong binding of HEDD -- as strong as that of its natural ligand, 17{beta}-estradiol (E2), the main human estrogen. However, an examination of the virtual binding pocket revealed that at least one residue near the critical ligand-binding site of their reported HEDD-ER complex was labelled as "unknown" indicating thereby alteration of the receptors published structure (Tannenbaum et al, 1998; Bafna et al., 2020) to fit the ligand. Based on these arguments, the contradictory result by Canario et al. (2022) on HEDDs binding to ER should be dismissed. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=102 SRC="FIGDIR/small/501604v2_fig1.gif" ALT="Figure 1"> View larger version (24K): org.highwire.dtl.DTLVardef@488472org.highwire.dtl.DTLVardef@ef7642org.highwire.dtl.DTLVardef@13d1ff4org.highwire.dtl.DTLVardef@1fce259_HPS_FORMAT_FIGEXP M_FIG O_FLOATNOFigure 1.C_FLOATNO (A) Schematic illustration of CNS-selective reductive bioactivation of bioprecursor prodrugs shown in panel B to the corresponding estrogen (E2, E2 or E1). (B) Chemical structures of bioprecursor prodrugs of estrogens: 10,17-dihydroxyestra-1,4-dien-3-one (DHED) for E2; 10,17-dihydroxyestra-1,4-dien-3-one (DHED) for E2, and 10-hydroxyestra-1,4-dien-3,17-dione (HEDD) for E1 (Prokai-Tatrai and Prokai, 2018). C_FIG