Novel sst2-Selective Somatostatin Agonists. Three-Dimensional Consensus Structure by NMR
| Autor: | Jean Rivier, Jean Claude Reubi, Christy R. Grace, Roland Riek, Steven C. Koerber, Judit Erchegyi |
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| Rok vydání: | 2006 |
| Předmět: |
Models
Molecular chemistry.chemical_classification Agonist Molecular model Protein Conformation medicine.drug_class Stereochemistry Stereoisomerism Nuclear magnetic resonance spectroscopy Article Cyclic peptide Structure-Activity Relationship Protein structure chemistry Drug Discovery medicine Humans Molecular Medicine Structure–activity relationship Receptors Somatostatin Pharmacophore Nuclear Magnetic Resonance Biomolecular Oligopeptides |
| Zdroj: | Journal of Medicinal Chemistry. 49:4487-4496 |
| ISSN: | 1520-4804 0022-2623 |
| Popis: | The three-dimensional NMR structures of six octapeptide agonist analogues of somatostatin (SRIF) in the free form are described. These analogues, with the basic sequence H-DPhe/Phe2-c[Cys3-Xxx7-DTrp8-Lys9-Thr10-Cys14]-Thr-NH2 (the numbering refers to the position in native SRIF), with Xxx7 being Ala/Aph, exhibit potent and highly selective binding to human SRIF type 2 (sst2) receptors. The backbone of these sst2-selective analogues have the usual type-II’ β-turn reported in the literature for sst2/3/5-subtype-selective analogues. Correlating biological results and NMR studies led to the identification of the side chains of DPhe2, DTrp8 and Lys9 as the necessary components of the sst2 pharmacophore. This is the first study to show that the aromatic ring at position 7 (Phe7) is not critical for sst2 binding and that it plays an important role in sst3 and sst5 binding. This pharmacophore is therefore different from that proposed by others for sst2/3/5 analogues. |
| Databáze: | OpenAIRE |
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