Rational discovery of novel nuclear hormone receptor antagonists

Nuclear hormone receptors (NRs) are potential targets for therapeutic appro aches to many clinical conditions, including cancer, diabetes, and neurolog ical diseases. The crystal structure of the ligand binding domain of agonis t-bound NRs enables the design of compounds with agonist activity. However, with the exception of the human estrogen receptor-alpha, the lack of antag onist-bound "inactive" receptor structures hinders the rational design of r eceptor antagonists. In this study, we present a strategy for designing suc h antagonists. We constructed a model of the inactive conformation of human retinoic acid receptor-alpha by using information derived from antagonist- bound estrogen receptor-alpha and applied a computer-based virtual screenin g algorithm to identify retinoic acid receptor antagonists. Thus, the curre ntly available crystal structures of NRs may be used for the rational desig n of antagonists, which could lead to the development of novel drugs for a variety of diseases.