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Rational discovery of novel nuclear hormone receptor antagonists
M Schapira1, B M Raaka, H H Samuels
1Structural Biology, Skirball Institute of Biomolecular Medicine, Departments of Medicine and Pharmacology, New York University School of Medicine, 550 First Avenue, New York, NY 10016, USA.
Summary
Designing nuclear hormone receptor antagonists is crucial for treating diseases. This study presents a new strategy using existing crystal structures to model inactive receptors, enabling the rational design of novel therapeutic drugs.
Area of Science:
- Biochemistry
- Molecular Biology
- Drug Discovery
Background:
- Nuclear hormone receptors (NRs) are key therapeutic targets for cancer, diabetes, and neurological diseases.
- Designing agonist-bound NR structures is established, but inactive NR structures are lacking for antagonist development.
- The human estrogen receptor-alpha is the only NR with available antagonist-bound structures.
Purpose of the Study:
- To develop a strategy for the rational design of nuclear hormone receptor antagonists.
- To overcome the limitation of lacking antagonist-bound NR structures.
- To identify novel retinoic acid receptor antagonists.
Main Methods:
- Modeled the inactive conformation of human retinoic acid receptor-alpha.
- Utilized structural information from antagonist-bound estrogen receptor-alpha.
- Employed a computer-based virtual screening algorithm.
Main Results:
- Successfully constructed a model of an inactive NR conformation.
- Identified potential retinoic acid receptor antagonists through virtual screening.
- Demonstrated the utility of existing NR crystal structures for antagonist design.
Conclusions:
- The presented strategy enables the rational design of NR antagonists.
- This approach can leverage existing NR crystal structures.
- Facilitates the development of novel therapeutics for various diseases.