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

Abstract

ABSTRACTThe lack of nuclear estrogen receptor (ERα and ERβ) bindings of 10β-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 Canário et al. (2022) reported a robust binding of HEDD (Figure 1B) to ERα. The authors claimed a strong binding of HEDD — as strong as that of its natural ligand, 17β-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–ERα complex was labelled as “unknown” indicating thereby alteration of the receptor’s published structure (Tannenbaum et al, 1998; Bafna et al., 2020) to fit the ligand. Based on these arguments, the contradictory result by Canário et al. (2022) on HEDD’s binding to ERα should be dismissed.