title: Rational discovery of novel nuclear hormone receptor antagonists.
abstract: Nuclear hormone receptors (NRs) are potential targets for therapeutic approaches to many clinical conditions, including cancer, diabetes, and neurological diseases. The crystal structure of the ligand binding domain of agonist-bound NRs enables the design of compounds with agonist activity. However, with the exception of the human estrogen receptor-alpha, the lack of antagonist-bound "inactive" receptor structures hinders the rational design of receptor antagonists. In this study, we present a strategy for designing such 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 screening algorithm to identify retinoic acid receptor antagonists. Thus, the currently available crystal structures of NRs may be used for the rational design of antagonists, which could lead to the development of novel drugs for a variety of diseases.
authors.affiliation: Structural 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.
authors.forename: M
authors.initials: M
authors.lastname: Schapira
authors.forename: B M
authors.initials: BM
authors.lastname: Raaka
authors.forename: H H
authors.initials: HH
authors.lastname: Samuels
authors.forename: R
authors.initials: R
authors.lastname: Abagyan
mesh_terms: D000465:Algorithms; D001665:Binding Sites; D003198:Computer Simulation; D018360:Crystallography, X-Ray; D016208:Databases, Factual; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D047628:Estrogen Receptor alpha; D005189:False Positive Reactions; D006367:HeLa Cells; D006727:Hormone Antagonists / Q000737:chemistry* / Q000494:pharmacology; D006728:Hormones / Q000819:agonists; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D009010:Monte Carlo Method; D011487:Protein Conformation; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists / Q000037:antagonists & inhibitors* / Q000737:chemistry; D011960:Receptors, Estrogen / Q000737:chemistry; D018168:Receptors, Retinoic Acid / Q000819:agonists / Q000037:antagonists & inhibitors / Q000737:chemistry; D000072482:Retinoic Acid Receptor alpha; D013329:Structure-Activity Relationship; D014162:Transfection; D000097768:Retinoic Acid Receptor gamma
chemical_list: D047628:Estrogen Receptor alpha; D006727:Hormone Antagonists; D006728:Hormones; D008024:Ligands; D018160:Receptors, Cytoplasmic and Nuclear; D011960:Receptors, Estrogen; D018168:Receptors, Retinoic Acid; D000072482:Retinoic Acid Receptor alpha; D000097768:Retinoic Acid Receptor gamma; C000607071:RARA protein, human; C082925:retinoic acid receptor beta