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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.

journal_name

J Med Chem

journal_title

Journal of medicinal chemistry

authors

Koerber SC,Rizo J,Struthers RS,Rivier JE

doi

10.1021/jm990118u

keywords:

subject

Has Abstract

pub_date

2000-03-09 00:00:00

pages

819-28

issue

5

eissn

0022-2623

issn

1520-4804

pii

jm990118u

journal_volume

43

pub_type

杂志文章

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