title: Binding mode of ecdysone agonists to the receptor: comparative modeling and docking studies.
abstract: Three-dimensional structure models of the ligand-binding domain of the ecdysone receptor of Heliothis virescens were built by the homology modeling technique from the crystal structures of nuclear receptors. Two models were created based both on known ligand-binding domain structures of the receptors with the highest sequence identity to the ecdysone receptor, and on those of steroid hormone receptors. The latter model, which was found to have better stereochemical quality and be in good agreement with the binding of the steroidal framework of the endogenous agonist 20-hydroxyecdysone, was used for docking studies. The docking of 20-hydroxyecdysone to the receptor model revealed that the ligand molecule can interact with the receptor in a similar manner to other steroid hormone-receptor complexes. The docking of a dibenzoylhydrazine agonist, chromafenozide, was performed based on the correspondences between the molecule and 20-dydroxyecdysone expected by molecular comparison. The interactions of the ligands with the receptor in the complexes modeled were investigated and found to be consistent with known structure-activity relationships.
authors.affiliation: Exploratory Chemistry Research Laboratories, Sankyo Co., Ltd., 2-58 Hiromachi 1-chome, Shinagawa-ku, 140-8710, Tokyo, Japan. kasuya@shina.sankyo.co.jp
authors.forename: Atsushi
authors.initials: A
authors.lastname: Kasuya
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Sawada
authors.forename: Yoshihisa
authors.initials: Y
authors.lastname: Tsukamoto
authors.forename: Keiji
authors.initials: K
authors.lastname: Tanaka
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Toya
authors.forename: Mikio
authors.initials: M
authors.lastname: Yanagi
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001578:Benzopyrans / Q000737:chemistry / Q000494:pharmacology; D001665:Binding Sites; D001667:Binding, Competitive; D004441:Ecdysterone / Q000737:chemistry / Q000494:pharmacology; D006834:Hydrazines / Q000737:chemistry / Q000494:pharmacology; D019476:Insect Proteins / Q000819:agonists / Q000737:chemistry* / Q000235:genetics; D008958:Models, Molecular; D008969:Molecular Sequence Data; D015394:Molecular Structure; D009036:Moths / Q000737:chemistry / Q000235:genetics; D011487:Protein Conformation; D011987:Receptors, Steroid / Q000819:agonists / Q000737:chemistry* / Q000235:genetics; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid
chemical_list: D001578:Benzopyrans; D006834:Hydrazines; D019476:Insect Proteins; D011987:Receptors, Steroid; C055469:ecdysone receptor; C056565:1,2-dibenzoyl-tert-butylhydrazine; C454111:chromafenozide; D004441:Ecdysterone; C082026:tebufenozide