title: Consensus bioactive conformation of cyclic GnRH antagonists defined by NMR and molecular modeling.
abstract: Little is known of the conformation of peptide hormones as they interact with their receptors for a number of reasons: peptide hormones are notoriously flexible in solution, their receptors are particularly complex, and there is strong evidence that receptor-ligand interaction leading to activation is a dynamic process. Insights into the active conformation of the decapeptide gonadotropin releasing hormone (GnRH) have been obtained previously from the solution structures of four constrained GnRH antagonists ¿cyclo(1-10)[Ac-Delta(3)-Pro(1),DCpa(2),DTrp(3,6),NMeLeu+ ++(7), betaAla(10)]GnRH (1), cyclo(4-10)[Ac-Delta(3)Pro(1),DFpa(2),DTrp(3), Asp(4),DNal(6),Dpr(10)]GnRH (2), dicyclo(4-10/5-8)[Ac-DNal(1), DCpa(2),DTrp(3),Asp(4),Glu(5),DArg(6),Lys(8),Dpr (10)]GnRH (3), and dicyclo(4-10/5-5'-8)[Ac-DNal(1),DCpa(2),DPal(3), Asp(4),Glu(5)(Gly), DArg(6),Dbu(8),Dpr(10)]GnRH (4)¿. However, the precise location of the N-terminal tripeptide in the highly potent (K(i) < 0.4 nM) 2-4 remained unclear due to the lack of constraints in this region. The NMR structure of the newly discovered and potent (K(i) = 0.24 nM) dicyclo(1-1'-5/4-10)[Ac-Glu(1)(Gly),DCpa(2),DTrp(3),As p(4),Dbu(5), DNal(6),Dpr(10)]GnRH (5) now allows the definition of the conformation of this region. A combined computational analysis (consensus forcing) of compounds 2-5, designed to explore the common conformations available to them that are simultaneously consistent with the NMR data corresponding to each compound, leads to a consensus structural model for the GnRH pharmacophore. This model shares some common features with the structure of the nonpeptidic GnRH mimetic T-98475. In the course of that comparative study, two additional contact points to those proposed by the authors are identified, suggesting that this model has predictive value.
authors.affiliation: The Clayton Foundation Laboratories for Peptide Biology, The Salk Institute, 10010 North Torrey Pines Road, La Jolla, California 92037, USA.
authors.forename: S C
authors.initials: SC
authors.lastname: Koerber
authors.forename: J
authors.initials: J
authors.lastname: Rizo
authors.forename: R S
authors.initials: RS
authors.lastname: Struthers
authors.forename: J E
authors.initials: JE
authors.lastname: Rivier
mesh_terms: D000818:Animals; D005260:Female; D007987:Gonadotropin-Releasing Hormone / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006727:Hormone Antagonists / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D066298:In Vitro Techniques; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D008968:Molecular Conformation; D010060:Ovulation / Q000187:drug effects; D010456:Peptides, Cyclic / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D010902:Pituitary Gland / Q000166:cytology / Q000378:metabolism; D011728:Pyridones / Q000737:chemistry / Q000378:metabolism; D051381:Rats; D012996:Solutions; D013876:Thiophenes / Q000737:chemistry / Q000378:metabolism
chemical_list: D006727:Hormone Antagonists; D010456:Peptides, Cyclic; D011728:Pyridones; D012996:Solutions; D013876:Thiophenes; D007987:Gonadotropin-Releasing Hormone; C115419:T 98475