Consensus bioactive conformation of cyclic GnRH antagonists defined by NMR and molecular modeling

Steven C. Koerber, Jose Rizo-Rey, R. Scott Struthers, Jean E. Rivier

Research output: Contribution to journalArticlepeer-review

32 Scopus citations


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-Δ3-Pro1,DCpa2,DTrp3,6,NMeLeu7,βAla10]GnRH (1), cyclo(4-10)[Ac-Δ3Pro1,DFpa2,DTrp3,Asp4,DNal6,Dpr10]GnRH (2), dicyclo(4-10/5-8)[Ac- DNal1,DCpa2,DTrp3,Asp4,Glu5,DArg6,Lys8,Dpr10]GnRH (3), and dicyclo(4-10/5-5'-8)[Ac- DNal1,DCpa2,DPal3,Asp4,Glu5(Gly),DArg6,Dbu8,Dpr10]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- Glu1(Gly),DCpa2,DTrp3,Asp4,Dbu5,DNal6,Dpr10]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.

Original languageEnglish (US)
Pages (from-to)819-828
Number of pages10
JournalJournal of Medicinal Chemistry
Issue number5
StatePublished - Mar 9 2000

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery


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