Conformational study of cyclo[Gln-Trp-Phe-Gly-Leu-Met] as NK-2 antagonist by NMR and molecular dynamics

Siahaan, Teruna J.; Lutz, Karen L.

doi:10.1016/0731-7085(94)80011-1

Cited by 6 publications

(1 citation statement)

References 12 publications

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“…The enhancement of antagonist activity and selectivity derived from cyclization, clearly showed that the favorable conformation for specific interaction with NK 2 receptor was mimicked. However, L659,877 still possesses a considerable conformational flexibility in solution, as ascertained by NMR analysis. − A further improvement was achieved by us with a more constrained analogue whose backbone could adopt a unique backbone conformation. A second cyclization through β functional groups inserted at positions 2 and 5 of L659,877 was performed, yielding the bicyclic peptide cyclo (Met 1 -Asp 2 -Trp 3 -Phe 4 -Dap 5 -Leu 6 ) cyclo (2β-5β) (Dap: (2 S )-2,3-diaminopropionic acid), named MEN10627. − This bicyclic peptide is the most potent NK 2 receptor antagonist described to date; it possesses high affinity for the NK 2 receptor, 10−100 fold higher than the parent monocyclic compound at the NK 2 receptor expressed in different species .…”

Section: Introductionmentioning

confidence: 99%

A Novel Rigid β-Turn Molecular Scaffold

et al. 1998

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We describe here the solution 1H NMR analysis, restrained and unrestrained molecular dynamic simulations of the bicyclic peptide cyclo(Met1-asp2-Trp3-Phe4-dap5-Leu6)cyclo(2β-5β) (MEN10701) (dap: (2R)-2,3-diaminopropionic acid). This compound is an analogue of cyclo(Met1-Asp2-Trp3-Phe4-Dap5-Leu6)cyclo(2β-5β) (MEN10627) (Dap: (2S)-2,3-diaminopropionic acid), which is the most potent and selective, peptide-based NK2 receptor antagonist known to date. MEN10701 differs from MEN10627 for the d chirality of the Asp2 and Dap5 residues; it was designed to better understand the role of the lactame bridge in determining the shape of the molecule and to elucidate whether its position, above or below the plane containing the pharmacophores (Met1, Trp3, Phe4, and Leu6 side chains), could modulate the biological response. Despite our expectations, the uncoercible bicyclic structure of MEN10627 is dramatically coerced into a novel conformation, by the replacement of the lactame bridge forming units (Asp2 and Dap5) with residues of opposite chirality. The overall shape of MEN10701 is also quite unique because of its compactness. It is ellipsoidal instead of being rectangle-like, and the structure is stabilized by two intramolecular hydrogen bonds encompassing two type I‘ β-turns. This structure can be added to the repertoire of rigid β-turn scaffolds for the design of bioactive molecules, which require turned motifs to elicit potency and specificity.

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Section: Introductionmentioning

confidence: 99%

A Novel Rigid β-Turn Molecular Scaffold

et al. 1998

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The study of the conformation and interaction of two tachykinin peptides in membrane mimicking systems by NMR spectroscopy and pulsed field gradient diffusion

Gao

Wong

1999

Biopolymers

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Conformational rigidity versus flexibility in a novel peptidic neurokinin A receptor antagonist

Pavone

Lombardi

Maggi

et al. 1995

Journal of Peptide Science

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Neurokinin A receptor antagonists have been proposed as a new class of drugs for several applications in humans (asthma, intestinal motility, etc.). The rational design, synthesis, structural characterization and biological activity evaluation of a new potent, highly selective, long-lasting, peptide-based receptor antagonist are reported. The structure-activity relationship indicates that the conformational rigidity determines potency, specificity and especially the long life of the molecule in the living body. MEN10627 is the prototype of a new class of cyclic, peptide-based, neurokinin A receptor antagonists and it is a suitable candidate for clinical testing in humans.

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Conformational study of cyclo[Gln-Trp-Phe-Gly-Leu-Met] as NK-2 antagonist by NMR and molecular dynamics

Cited by 6 publications

References 12 publications

A Novel Rigid β-Turn Molecular Scaffold

A Novel Rigid β-Turn Molecular Scaffold

The study of the conformation and interaction of two tachykinin peptides in membrane mimicking systems by NMR spectroscopy and pulsed field gradient diffusion

Conformational rigidity versus flexibility in a novel peptidic neurokinin A receptor antagonist

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