title: Efficient discovery of selective small molecule agonists of estrogen-related receptor gamma using combinatorial approach.
abstract: With the goal of discovering a selective agonist of estrogen-related receptor gamma (ERRgamma) with enhanced potency, we designed a series of small-molecule ligands derived from a known ERRgamma agonist, GSK4716, that can substantially potentiate the transcriptional activity of ERRgamma. Individual compounds among a 30-member library of acyl hydrazones were pre-evaluated through in silico docking studies on the receptor cavities of ERRgamma LBDs using X-ray crystal structures cocrystallized with GSK4716 and 4-OHT. This rational approach to achieve the enhanced potency in ERRgamma transcriptional activity with selectivity over ERRalpha/beta enables us to complete the construction of a focused library by carrying out microwave-assisted parallel synthesis with excellent yields and purities. Finally, we identified a more potent ERRgamma agonist, E6, with excellent selectivity over ERRalpha/beta.
authors.affiliation: Department of Chemistry, College of Natural Science, Seoul National University, Seoul 151-747, Korea.
authors.forename: Yongju
authors.initials: Y
authors.lastname: Kim
authors.forename: Minseob
authors.initials: M
authors.lastname: Koh
authors.forename: Don-Kyu
authors.initials: DK
authors.lastname: Kim
authors.forename: Hueng-Sik
authors.initials: HS
authors.lastname: Choi
authors.forename: Seung Bum
authors.initials: SB
authors.lastname: Park
mesh_terms: D020650:Combinatorial Chemistry Techniques; D018360:Crystallography, X-Ray; D055808:Drug Discovery; D006834:Hydrazines / Q000737:chemistry / Q000494:pharmacology; D008958:Models, Molecular; D015394:Molecular Structure; D011960:Receptors, Estrogen / Q000819:agonists*; D013629:Tamoxifen / Q000031:analogs & derivatives / Q000737:chemistry / Q000494:pharmacology
chemical_list: C490917:ESRRG protein, human; C545235:GSK 4716; D006834:Hydrazines; D011960:Receptors, Estrogen; D013629:Tamoxifen; C016601:afimoxifene