title: Protein structure based rational design of ecdysone agonists.
abstract: We review the impact of protein X-ray crystallography on the rational design of insecticides that act as agonists of the ligand-binding domain of the Ecdysone receptor (EcR). As the EcR is a target specific to insects, these compounds potentially constitute new chemical classes of safe insecticides. The increased insight relative to that from ligand-only based (Quantitative) Structure-Activity Relations (QSARs), classical 2D-Hansch type or 3D-CoMFA/CoMSIA (Comparative Molecular Field/Similarity Analysis), is discussed. The importance of protein X-ray structure determination in support of the discovery process is stressed as the simplistic lock-and-key picture fails due to the remarkable flexibility of the EcR ligand binding site. Several new non-steroidal chemical classes of ecdysone agonists, designed by guidance from protein X-ray studies, are described.
authors.affiliation: Bayer CropScience AG, Alfred-Nobel-Str. 50, 40789 Monheim, Germany.
authors.forename: Graham
authors.initials: G
authors.lastname: Holmwood
authors.forename: Michael
authors.initials: M
authors.lastname: Schindler
mesh_terms: D017076:Computer-Aided Design; D018360:Crystallography, X-Ray; D006834:Hydrazines / Q000737:chemistry; D007306:Insecticides / Q000737:chemistry*; D017434:Protein Structure, Tertiary; D021281:Quantitative Structure-Activity Relationship; D011987:Receptors, Steroid / Q000819:agonists* / Q000378:metabolism
chemical_list: D006834:Hydrazines; D007306:Insecticides; D011987:Receptors, Steroid; C055469:ecdysone receptor; C029424:hydrazine