Compound 4a was found to be too big for the accommodation in the estradiol-binding pocket of ERa in the structure 1GWR. Meanwhile, the ligands TFMPV-E2 (PDB: 2P15) and EEu (PDB: 2YAT) are known to modulate the dynamics of the ERα helix 12 (shown in red, Figures 3A–D), resulting in an increase in the ligand-binding pocket surface of ER without changing the shape of the ligand-binding domain of ER due to the presence of bulky substituents at the 17α position of the estradiol core (Eignerova et al., 2010; Gryder et al., 2013). Compound 4a bearing the bulky dihydrotriazine ring at the 16-position is docked against the ERα crystal structures 2P15 and 2YAT with reasonable binding affinity (−8.1 and −8.9 kcal/mol, respectively). However, the major binding modes of compound 4a for 2P15 and 2YAT are as follows: the A-ring phenolic hydroxyl group points away the binding pocket of ER and the dihydrotriazine moiety points inward the binding pocket. The critical hydrogen-bonding interactions between the steroid estradiol, TFMPV-E2 and the A-ring phenolic hydroxyls of EEu with Arg-394/Glu-353 were not found for compound 4a (Figures 3A–C), which can be attributed to steric hindrance caused by the bulky substituent at the 16-position and spatial aliasing of the estrane core due to the addition of the C16 = C17 double bond.