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Conformational analyses of cyclic hexapeptide analogs of somatostatin containing arylalkyl peptoid and naphthylalanine residues
Author(s) -
Mattern RalphHeiko,
Tran ThuyAnh,
Goodman Murray
Publication year - 1999
Publication title -
journal of peptide science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.475
H-Index - 66
eISSN - 1099-1387
pISSN - 1075-2617
DOI - 10.1002/(sici)1099-1387(199904)5:4<161::aid-psc177>3.0.co;2-f
Subject(s) - peptoid , chemistry , stereochemistry , molecular dynamics , molecular model , peptide , molecule , cyclic peptide , biochemistry , computational chemistry , organic chemistry
We report the conformational analysis by 1 H‐NMR in DMSO and computer simulations involving distance geometry and molecular dynamics simulations of peptoid analogs of the cyclic hexapeptide c ‐[Phe 11 ‐Pro 6 ‐Phe 7 ‐ d ‐Trp 8 ‐Lys 9 ‐Thr 10 ] L‐363,301 (the numbering refers to the positions in native somatostatin). The compounds c ‐[Phe 11 ‐Nphe 6 ‐Nal 7 ‐ d ‐Trp 8 ‐Lys 9 ‐Thr 10 ] ( Nphe 6 ‐ Nal 7 analog 1 ), c ‐[Nal 11 ‐Nphe 6 ‐Phe 7 ‐ d ‐Trp 8 ‐Lys 9 ‐Thr 10 ] ( Nal 11 ‐ Nphe 6 analog 2 ) and c ‐[Phe 11 ‐Nnal 6 ‐Phe 7 ‐ d ‐Trp 8 ‐Lys 9 ‐Thr 10 ] ( Nnal 6 analog 3 ), where Nphe denotes N ‐benzylglycine and Nnal denotes N ‐(1‐naphthylmethyl)glycine, are subjected to SAR studies in order to investigate the influence of the bulky naphthyl aromatic ring on the conformation. The Nal 11 ‐ Nphe 6 and Nphe 6 ‐Nal 7 analogs exhibit potent binding to the hsst2, hsst3 and hsst5 receptors, whereas the Nnal 6 analog has decreased binding affinity to all receptors but is more selective towards the hsst2 than the other two analogs and L‐363,301. The conformational search employing distance geometry, energy minimization and molecular dynamic simulations gives insight into the conformational flexibility of these analogs. The molecules adopt both cis and trans orientations of the peptide bond between residues 11 and 6. The cis isomers of these analogs adopt type II′ β‐turns with d ‐Trp in the i +1 position and type VI a β‐turns with the cis peptide bond between residues 6 and 11. The results of free and distance restrained molecular dynamics simulations at 300 K indicate that the Nphe 6 ‐Nal 7 and Nal 11 ‐Nphe 6 compounds adopt a preferred backbone conformation which can be described as ‘folded’ about residues 7 and 10. The Nnal 6 analog, which binds less effectively to the hsst receptors, has a more flexible backbone structure than the Nal 11 ‐Nphe 6 and Nphe 6 ‐Nal 7 analogs and prefers a ‘flat’ structure with regard to the orientations about Phe 7 and Thr 10 during molecular dynamics simulations. Copyright © 1999 European Peptide Society and John Wiley & Sons, Ltd.