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

Publication ,  Journal Article
Reddy Sammeta, V; Anderson, BM; Norris, JD; Torrice, CD; Joiner, C; Liu, S; Li, H; Popov, KI; Fanning, SW; McDonnell, DP; Willson, TM
Published in: Helvetica Chimica Acta
September 1, 2023

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.

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Published In

Helvetica Chimica Acta

DOI

EISSN

1522-2675

ISSN

0018-019X

Publication Date

September 1, 2023

Volume

106

Issue

9

Related Subject Headings

  • General Chemistry
  • 34 Chemical sciences
  • 03 Chemical Sciences
 

Citation

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Reddy Sammeta, V., Anderson, B. M., Norris, J. D., Torrice, C. D., Joiner, C., Liu, S., … Willson, T. M. (2023). Structural Determinants of the Binding and Activation of Estrogen Receptor α by Phenolic Thieno[2,3-d]pyrimidines. Helvetica Chimica Acta, 106(9). https://doi.org/10.1002/hlca.202300097
Reddy Sammeta, V., B. M. Anderson, J. D. Norris, C. D. Torrice, C. Joiner, S. Liu, H. Li, et al. “Structural Determinants of the Binding and Activation of Estrogen Receptor α by Phenolic Thieno[2,3-d]pyrimidines.” Helvetica Chimica Acta 106, no. 9 (September 1, 2023). https://doi.org/10.1002/hlca.202300097.
Reddy Sammeta V, Anderson BM, Norris JD, Torrice CD, Joiner C, Liu S, et al. Structural Determinants of the Binding and Activation of Estrogen Receptor α by Phenolic Thieno[2,3-d]pyrimidines. Helvetica Chimica Acta. 2023 Sep 1;106(9).
Reddy Sammeta, V., et al. “Structural Determinants of the Binding and Activation of Estrogen Receptor α by Phenolic Thieno[2,3-d]pyrimidines.” Helvetica Chimica Acta, vol. 106, no. 9, Sept. 2023. Scopus, doi:10.1002/hlca.202300097.
Reddy Sammeta V, Anderson BM, Norris JD, Torrice CD, Joiner C, Liu S, Li H, Popov KI, Fanning SW, McDonnell DP, Willson TM. Structural Determinants of the Binding and Activation of Estrogen Receptor α by Phenolic Thieno[2,3-d]pyrimidines. Helvetica Chimica Acta. 2023 Sep 1;106(9).
Journal cover image

Published In

Helvetica Chimica Acta

DOI

EISSN

1522-2675

ISSN

0018-019X

Publication Date

September 1, 2023

Volume

106

Issue

9

Related Subject Headings

  • General Chemistry
  • 34 Chemical sciences
  • 03 Chemical Sciences