To gain further insight into how the differences in H-bonding of the phenols in 1, 2, and 3 with the ERa LBD could affect their activity, we performed a series of density functional theory (DFT) calculations. From the X-ray co-crystal structures, three models were constructed using the ligands 1-3 and the atoms from the amino acids in the first shell of the binding pocket, comprising >500 atoms in each case. All hydrogen atoms of the models were optimized at the DFT M062X/6-31G(d) level of theory and basis set superposition error (BSSE) corrected calculations performed at two theoretical levels using 6-311+G(d) basis set for O, N, Cl, and S elements and 6-311G(d) basis set for C and H elements using Gaussian. As shown in Table , the meta-phenol (2) showed the highest binding energy in both DFT models, with the para-phenol (1) producing values ~10 kcal/mol lower energy and the isoindolin-5-ol (3) returning intermediate values. The calculations appeared to reflect the additional H-bonding interactions that were observed in the meta-phenol (2) and isoindolin-5-ol (3) X-ray crystal structures and did not explain the improved activity of para-phenol (1) as an ERa ligand.