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Consensus Bioactive Conformation of Cyclic GnRH Antagonists Defined by NMR and Molecular Modeling

2000; American Chemical Society; Volume: 43; Issue: 5 Linguagem: Inglês

10.1021/jm990118u

1520-4804

Steven C. Koerber, Josep Rizo, R. Scott Struthers, Jean Rivier,

Receptor Mechanisms and Signaling

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 (Ki < 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 (Ki = 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.