Structural Determinants of the Binding and Activation of Estrogen Receptor α by Phenolic Thieno[2,3‐d]pyrimidines

Synthetic, structural, and computational approaches were used to solve the puzzle as to how a phenolic nonsteroidal estrogen 1 with only a single H‐bond to its receptor was more potent than an isomer 2 which formed an intricate network of H‐bonds. Synthesis of a series of substituted phenols revealed that p K a was not a determinant of estrogenic activity. First‐principles calculation also failed to explain the difference in activity of 1 and 2 . Molecular dynamics revealed that 1 formed a more stable receptor complex compared to 2 , which may explain its increased activity despite forming fewer apparent H‐bonds with the protein.