title: Synthesis, binding and bioactivity of gamma-methylene gamma-lactam ecdysone receptor ligands: advantages of QSAR models for flexible receptors.
abstract: Nuclear hormone receptors, such as the ecdysone receptor, often display a large amount of induced fit to ligands. The size and shape of the binding pocket in the EcR subunit changes markedly on ligand binding, making modelling methods such as docking extremely challenging. It is, however, possible to generate excellent 3D QSAR models for a given type of ligand, suggesting that the receptor adopts a relatively restricted number of binding site configurations or 'attractors'. We describe the synthesis, in vitro binding and selected in vivo toxicity data for gamma-methylene gamma-lactams, a new class of high-affinity ligands for ecdysone receptors from Bovicola ovis (Phthiraptera) and Lucilia cuprina (Diptera). The results of a 3D QSAR study of the binding of methylene lactams to recombinant ecdysone receptor protein suggest that this class of ligands is indeed recognised by a single conformation of the EcR binding pocket.
authors.affiliation: CSIRO Molecular and Health Technologies, Ian Wark Laboratory, Bag 10, Clayton South, Vic 3169, Australia.
authors.forename: Woldeamanuel
authors.initials: W
authors.lastname: Birru
authors.forename: Ross T
authors.initials: RT
authors.lastname: Fernley
authors.forename: Lloyd D
authors.initials: LD
authors.lastname: Graham
authors.forename: Julian
authors.initials: J
authors.lastname: Grusovin
authors.forename: Ronald J
authors.initials: RJ
authors.lastname: Hill
authors.forename: Albert
authors.initials: A
authors.lastname: Hofmann
authors.forename: Linda
authors.initials: L
authors.lastname: Howell
authors.forename: Peter J
authors.initials: PJ
authors.lastname: James
authors.forename: Karen E
authors.initials: KE
authors.lastname: Jarvis
authors.forename: Wynona M
authors.initials: WM
authors.lastname: Johnson
authors.forename: Dionne A
authors.initials: DA
authors.lastname: Jones
authors.forename: Christa
authors.initials: C
authors.lastname: Leitner
authors.forename: Andris J
authors.initials: AJ
authors.lastname: Liepa
authors.forename: George O
authors.initials: GO
authors.lastname: Lovrecz
authors.forename: Louis
authors.initials: L
authors.lastname: Lu
authors.forename: Roland H
authors.initials: RH
authors.lastname: Nearn
authors.forename: Brian J
authors.initials: BJ
authors.lastname: O'Driscoll
authors.forename: Tram
authors.initials: T
authors.lastname: Phan
authors.forename: Matthew
authors.initials: M
authors.lastname: Pollard
authors.forename: Kathleen A
authors.initials: KA
authors.lastname: Turner
authors.forename: David A
authors.initials: DA
authors.lastname: Winkler
mesh_terms: D000081:Acetamides / Q000138:chemical synthesis / Q000737:chemistry / Q000633:toxicity; D001665:Binding Sites; D003198:Computer Simulation; D008024:Ligands; D021281:Quantitative Structure-Activity Relationship; D011987:Receptors, Steroid / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D000081:Acetamides; D008024:Ligands; D011987:Receptors, Steroid; D011994:Recombinant Proteins; C055469:ecdysone receptor