Conformational study of three endothelin antagonists with <sup>1</sup>H NMR at low temperature and molecular dynamics

Verheyden, Patricia; Assche, Ivo Van; Brichard, M.‐H.; Demaude, Thierry; Paye, Ingrid; Scarso, A.; Binst, G. Van

doi:10.1016/0014-5793(94)00352-1

Cited by 6 publications

(3 citation statements)

References 12 publications

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“…Structural studies of peptide I using a combination of NMR and molecular dynamics suggest a cyclic conformation for this peptide in solution. 7 To test the possible relevance of such a conformation to GnRH receptor recognition, we have synthesized a head-to-tail cyclic analogue of the deacetylated peptide Ile-Ile-Trp-D-Trp-Leu-Asp (peptide III, Figure 1). This modification resulted in an undetectable ET receptor binding, in an increased GnRH binding affinity (Table 1), and in increased LH releasing activity (Figure 2).…”

Section: Resultsmentioning

confidence: 99%

“…Structural studies of peptide I using a combination of NMR and molecular dynamics suggest a cyclic conformation for this peptide in solution . To test the possible relevance of such a conformation to GnRH receptor recognition, we have synthesized a head-to-tail cyclic analogue of the deacetylated peptide (peptide III, Figure ).…”

Section: Resultsmentioning

confidence: 99%

“…Gonadotropin-releasing hormone (GnRH) is a neurohormone that is secreted from the hypothalamus in a pulsatile pattern and regulates the reproductive system by controlling the secretion of the gonadotropic hormones, luteinizing hormone (LH), and follicle stimulating hormone (FSH) from the anterior pituitary. , On the basis of conformational energy calculations and various physicochemical methods, it was suggested that the bioactive conformation of GnRH include a type II‘ β turn involving residues 5−8 {Tyr-Gly-Leu-Arg}.…”

Section: Introductionmentioning

confidence: 99%

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Structure−Activity Studies of Reduced-Size Gonadotropin-Releasing Hormone Agonists Derived from the Sequence of an Endothelin Antagonist

et al. 2000

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We have previously determined that Ac-D-Trp-Leu-Asp-Ile-Ile-Trp (peptide I), an endothelin antagonist, binds specifically (Ki = 1.9 microM) to the rat pituitary gonadotropin-releasing hormone (GnRH) receptor. Moreover, peptide I exhibits a GnRH agonistic activity, mediated directly by the GnRH receptor. We now report structure-activity studies of peptide I in respect to its interactions with the GnRH receptor. Our studies suggest that the bioactive conformation of peptide I, recognized by the GnRH receptor, is of a cyclic nature. Thus cyclic analogues of peptide I exhibit higher affinity to the GnRH receptor and increased agonistic potencies as compared to peptide I itself. A linear peptide, Ile-Ile-Trp-D-Trp-Leu-Asp, which presumably forms a similar cyclic conformation, was also shown to be a GnRH agonist. Intraperitoneal administration of Ac-Ile-Ile-Trp-D-Trp-Leu-Cys-OH (Ki = 0.32 microM), one of the cyclic hexapeptides that we have synthesized, to rats induces secretion of luteinizing hormone (LH) with a potency which is only 1 order of magnitude less than that of GnRH itself. Moreover, plasma levels of LH remained elevated for a longer period of time following the administration of the cyclic hexapeptide. This novel class of GnRH agonists may prove useful in the development of new therapeutics.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Structure−Activity Studies of Reduced-Size Gonadotropin-Releasing Hormone Agonists Derived from the Sequence of an Endothelin Antagonist

et al. 2000

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SONHICA (Simple optimized non-HIerarchical Cluster Analysis): A new tool for analysis of molecular conformations

et al. 1997

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We describe a new clustering program, SONHICA (Simple Optimized Non‐HIerarchical Cluster Analysis), developed to analyze large data sets of molecular conformations. Unlike traditional clustering methods, SONHICA does not make use of an overall index, like a distance, to evaluate similarity between objects. Each descriptor variable is compared individually on the basis of a preset threshold value. This assures high control and sensitivity over the input variables. In addition, periodic and nonperiodic descriptors, such as dihedral angles and interatomic distances, can easily be used together. SONHICA generates clusters with the highest possible density and all pairs of objects within a cluster are similar. These features make SONHICA particularly suitable for the analysis of data sets which tend to form globular clusters. This method was applied to the analysis of a modified linear tetrapeptide, ITF1697, under investigation for its anti‐ischemic properties, and a cyclic pentapeptide, BQ123, a potent antagonist of endothelin A. On the basis of the results presented here, SONHICA appears to be an interesting new tool in the field of the clustering methods applied to the analysis of molecular conformations. © 1997 John Wiley & Sons, Inc. J Comput Chem 18: 1295–1311, 1997

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The development of potent peptide agonists and antagonists for the endothelin receptors

Cody¹,

Doherty²

1995

Biopolymers

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The endothelins (ETs), sarafotoxins (SRTXs), vasoactive intestinal contractor (VIC), and bibrotoxin are a family of potent vasoconstrictor peptides. All peptides in this family possess 21 amino acids arranged in a unique bicyclic motif formed between cystine bridges in the 1-15 and 3-11 positions. Since the discovery of endothelin-1 (ET-1) in 1988, significant effort has been focused on the understanding of its structure-activity relationships. The identification of endothelin receptor subtypes has led to the discovery/design of potent peptide agonists and antagonists, along with nonpeptide antagonists of endothelin with varying levels of potency and receptor subtype selectivity. In keeping with the theme of this journal, this review will focus only on the development of peptidic-based agonists and antagonists of endothelin in addition to their applications in understanding the physiological and/or pathophysiological role of endothelin and its isopeptides.

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Conformational study of three endothelin antagonists with ¹H NMR at low temperature and molecular dynamics

Cited by 6 publications

References 12 publications

Structure−Activity Studies of Reduced-Size Gonadotropin-Releasing Hormone Agonists Derived from the Sequence of an Endothelin Antagonist

Structure−Activity Studies of Reduced-Size Gonadotropin-Releasing Hormone Agonists Derived from the Sequence of an Endothelin Antagonist

SONHICA (Simple optimized non-HIerarchical Cluster Analysis): A new tool for analysis of molecular conformations

The development of potent peptide agonists and antagonists for the endothelin receptors

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Conformational study of three endothelin antagonists with 1H NMR at low temperature and molecular dynamics

Cited by 6 publications

References 12 publications

Structure−Activity Studies of Reduced-Size Gonadotropin-Releasing Hormone Agonists Derived from the Sequence of an Endothelin Antagonist

Structure−Activity Studies of Reduced-Size Gonadotropin-Releasing Hormone Agonists Derived from the Sequence of an Endothelin Antagonist

SONHICA (Simple optimized non-HIerarchical Cluster Analysis): A new tool for analysis of molecular conformations

The development of potent peptide agonists and antagonists for the endothelin receptors

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Conformational study of three endothelin antagonists with ¹H NMR at low temperature and molecular dynamics