Conformational analysis of a highly potent dicyclic gonadotropin-releasing hormone antagonist by nuclear magnetic resonance and molecular dynamics

Rachelle J. Bienstock, Jose Rizo-Rey, Steven C. Koerber, Jean E. Rivier, Arnold T. Hagler, Lila M. Gierasch

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Abstract

Structural analysis of constrained (monocyclic) analogues of gonadotropin-releasing hormone (GnRH) has led to the development of a model for the receptor-bound conformation of GnRH and to the design of highly potent, dicyclic GnRH antagonists. This is one of the first cases where a dicyclic backbone has been introduced into analogues of a linear peptide hormone with retention of high biological activity. Here we present a conformational analysis of dicyclo(4-10,5-8)[Ac-D-2Nal1-D-pClPhe2-D-Trp 3-Asp4-Glu5-D-Arg6-Leu 7-Lys8-Pro9-Dpr10]-NH2 (I), using two-dimensional nuclear magnetic resonance (NMR) spectroscopy and molecular dynamics simulation. Compound I inhibits ovulation in the rat at a dose of 5-10 μg (Rivier et al. In Peptides: Chemistry, Structure ad Biology; Rivier, J. E., Marshall, G. R., Eds.; ESCOM: Leiden, The Netherlands, 1990; pp 33-37). The backbone conformation of the 4-10 cycle in this dicyclic compound is very similar to that found previously for a parent monocyclic (4-10) GnRH antagonist (Rizo et al. J. Am. Chem. Soc. 1992, 114, 2852-2859; ibid. 2860-2871), which gives strong support to the hypothesis that GnRH adopts a similar conformation upon binding to its receptor. In this conformation, residues 5-8 form a "β-hairpin-like" structure that includes two transannular hydrogen bonds and a Type II′ β turn around residues D-Arg6-Leu7. The "tail" of the molecule formed by residues 1-3 is somewhat structured but does not populate a single major conformation. However, the orientation of the tail on the same side of the 4-10 cycle as the 5-8 bridge favors interactions between this bridge and the tail residues. These observations correlate with results obtained previously for the parent monocyclic (4-10) antagonist, and have led to the design of a series of new dicyclic GnRH antagonists with bridges between the tail residues and residues 5 or 8.

Original languageEnglish (US)
Pages (from-to)3265-3273
Number of pages9
JournalJournal of Medicinal Chemistry®
Volume36
Issue number22
StatePublished - 1993

Fingerprint

Hormone Antagonists
Molecular Dynamics Simulation
Gonadotropin-Releasing Hormone
Molecular dynamics
Magnetic Resonance Spectroscopy
Nuclear magnetic resonance
Conformations
Tail
Peptide Hormones
Ovulation
Bioactivity
Structural analysis
Crystal orientation
Netherlands
Nuclear magnetic resonance spectroscopy
Rats
Hydrogen
Hydrogen bonds
Peptides
Molecules

ASJC Scopus subject areas

  • Organic Chemistry

Cite this

Conformational analysis of a highly potent dicyclic gonadotropin-releasing hormone antagonist by nuclear magnetic resonance and molecular dynamics. / Bienstock, Rachelle J.; Rizo-Rey, Jose; Koerber, Steven C.; Rivier, Jean E.; Hagler, Arnold T.; Gierasch, Lila M.

In: Journal of Medicinal Chemistry®, Vol. 36, No. 22, 1993, p. 3265-3273.

Research output: Contribution to journalArticle

Bienstock, Rachelle J. ; Rizo-Rey, Jose ; Koerber, Steven C. ; Rivier, Jean E. ; Hagler, Arnold T. ; Gierasch, Lila M. / Conformational analysis of a highly potent dicyclic gonadotropin-releasing hormone antagonist by nuclear magnetic resonance and molecular dynamics. In: Journal of Medicinal Chemistry®. 1993 ; Vol. 36, No. 22. pp. 3265-3273.
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T1 - Conformational analysis of a highly potent dicyclic gonadotropin-releasing hormone antagonist by nuclear magnetic resonance and molecular dynamics

AU - Bienstock, Rachelle J.

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AU - Rivier, Jean E.

AU - Hagler, Arnold T.

AU - Gierasch, Lila M.

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