A series of molecular dynamics (MD) simulations was performed to explore the idea that activity of the phenolic thieno [2,3-d]pyrimidines in the ERa LiSA and reporter gene assays was the result of a complex dynamic of receptor binding and stabilization of the hormone receptor in an active conformation. MD simulations were performed over 100 ps using structures prepared from the X-ray coordinates of 1, 2, and 3 with ERa LBD (PDB: 7RKE, 7SFO, and 7RNM, respectively) that included the structural water molecules within 8 Å of E353, R394, and the ligand. The MD simulations revealed some significant differences in the ligand-residue distances and ligand-induced protein conformation changes (Figure ). The distribution of distances of the phenol to each of three key residues (E353, L349 and R394) in the ligand binding pocket was determined. The results indicated that para-phenol (1) (Figure , pink) was located closer to L349 during the time of the simulations compared to meta-phenol (2) (Figure , blue) and isoindolin-5-ol (3) (Figure , green). The para-phenol (1) trajectory also showed a tighter unimodal distribution of the ligand in its interaction distances with E353 and R394, consistent with its higher potency. Analysis of binding site residues root-mean-square fluctuations (RMSF) (Figure ) revealed greater stabilization of R394 by para-phenol (1) compared to meta-phenol (2) with isoindolin-5-ol (3) producing an intermediate stabilization.