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

03 July 2023, Version 1
This content is a preprint and has not undergone peer review at the time of posting.


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 pKa 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.


estrogen receptor
density functional calculations
ligand effects
molecular dynamics
structure-activity relationships

Supplementary materials

Supporting Information
Figure S1 – Competition binding data for 1 and 2. Figure S2 – Atom count from the amine N to phenol O for 1, 2, 3. Figure S3 – 1H NMR chemical shift of the phenol in 1, 2, and 4–13. Table S1 – X-ray crystallographic refinement data. NMR spectra of final compounds 1–13.


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