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Structure-based design of estrogen receptor-β selective ligands

Journal of the American Chemical Society, ISSN: 0002-7863, Vol: 126, Issue: 46, Page: 15106-15119
2004
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Article Description

We present the structure-based optimization of a series of estrogen receptor-β (ERβ) selective ligands. X-ray cocrystal structures of these ligands complexed to both ERα and ERβ are described. We also discuss how molecular modeling was used to take advantage of subtle differences between the two binding cavities in order to optimize selectivity for ERβ over ERα. Quantum chemical calculations are utilized to gain insight into the mechanism of selectivity enhancement. Despite only two relatively conservative residue substitutions in the ligand binding pocket, the most selective compounds have greater than 100-fold selectivity for ERβ relative to ERα when measured using a competitive radioligand binding assay.

Bibliographic Details

Manas, Eric S; Unwalla, Rayomand J; Xu, Zhang B; Malamas, Michael S; Miller, Chris P; Harris, Heather A; Hsiao, Chulai; Akopian, Tatos; Hum, Wah-Tung; Malakian, Karl; Wolfrom, Scott; Bapat, Ashok; Bhat, Ramesh A; Stahl, Mark L; Somers, William S; Alvarez, Juan C

American Chemical Society (ACS)

Chemical Engineering; Chemistry; Biochemistry, Genetics and Molecular Biology

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