Journal
CHEMMEDCHEM
Volume 6, Issue 4, Pages 654-666Publisher
WILEY-V C H VERLAG GMBH
DOI: 10.1002/cmdc.201000507
Keywords
coactivator binding inhibitors; estrogen antagonists; estrogen receptors; molecular modeling; structure-activity relationships
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Funding
- US National Institutes of Health (NIH) [HG003918, DK015556]
- NIH [R37 DK015556, X01 MH078953, U54 HG003018]
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Small molecules, namely coactivator binding inhibitors (CBIs), that block estrogen signaling by directly inhibiting the interaction of the estrogen receptor (ER) with coactivator proteins act in a fundamentally different way to traditional antagonists, which displace the endogenous ligand estradiol. To complement our prior efforts at CBI discovery by de novo design, we used high-throughput screening (HTS) to identify CBIs of novel structure and subsequently investigated two HTS hits by analogue synthesis, finding many compounds with low micromolar potencies in cell-based reporter gene assays. We examined structure-activity trends in both series, using induced-fit computational docking to propose binding poses for these molecules in the coactivator binding groove. Analysis of the structure of the ER-steroid receptor coactivator (SRC) complex suggests that all four hydrophobic residues within the SRC nuclear receptor box sequence are important binding elements. Thus, insufficient water displacement upon binding of the smaller CBIs in the expansive complexation site may be limiting the potency of the compounds in these series, which suggests that higher potency CBIs might be found by screening compound libraries enriched with larger molecules.
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