Synthesis, binding and bioactivity of gamma-methylene gamma-lactam ecdysone receptor ligands: advantages of QSAR models for flexible receptors.
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.
Birru
Woldeamanuel
W
CSIRO Molecular and Health Technologies, Ian Wark Laboratory, Bag 10, Clayton South, Vic 3169, Australia.
Fernley
Ross T
RT
Graham
Lloyd D
LD
Grusovin
Julian
J
Hill
Ronald J
RJ
Hofmann
Albert
A
Howell
Linda
L
James
Peter J
PJ
Jarvis
Karen E
KE
Johnson
Wynona M
WM
Jones
Dionne A
DA
Leitner
Christa
C
Liepa
Andris J
AJ
Lovrecz
George O
GO
Lu
Louis
L
Nearn
Roland H
RH
O'Driscoll
Brian J
BJ
Phan
Tram
T
Pollard
Matthew
M
Turner
Kathleen A
KA
Winkler
David A
DA
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
D000081:Acetamides; D008024:Ligands; D011987:Receptors, Steroid; D011994:Recombinant Proteins; C055469:ecdysone receptor