Journal
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
Volume 56, Issue 20, Pages 5480-5484Publisher
WILEY-V C H VERLAG GMBH
DOI: 10.1002/anie.201612504
Keywords
drug design; drug discovery; natural products; spiro compounds; structure elucidation
Categories
Funding
- Dutch Ministry of Education, Culture, Science [024.001.035]
- ECHO grant [711011017]
- ECHO-STIP grant [717.014.004]
- CRC [1093]
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Spiroketals are structural motifs found in many biologically active natural products, which has stimulated considerable efforts toward their synthesis and interest in their use as drug lead compounds. Despite this, the use of spiroketals, and especially bisbenzanulated spiroketals, in a structure-based drug discovery setting has not been convincingly demonstrated. Herein, we report the rational design of a bisbenzannulated spiroketal that potently binds to the retinoid X receptor (RXR) thereby inducing partial coactivator recruitment. We solved the crystal structure of the spiroketal-hRXR alpha-TIF2 ternary complex, and identified a canonical allosteric mechanism as a possible explanation for the partial agonist behavior of our spiroketal. Our cocrystal structure, the first of a designed spiroketal-protein complex, suggests that spiroketals can be designed to selectively target other nuclear receptor subtypes.
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