A Novel Rigid -Turn Molecular Scaffold
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- 作者：Angela Lombardi ; Gabriella D'Auria ; Ornella Maglio ; Flavia Nastri ; Laura Quartara ; Carlo Pedone ; and Vincenzo Pavone
- 刊名：Journal of the American Chemical Society
- 出版年：1998
- 出版时间：June 24, 1998
- 年：1998
- 卷：120
- 期：24
- 页码：5879 - 5886
- 全文大小：106K
- 年卷期：v.120,no.24(June 24, 1998)
- ISSN：1520-5126
文摘
We describe here the solution 1H NMR analysis,restrained and unrestrained molecular dynamicsimulations of the bicyclic peptidecyclo(Met1-asp2-Trp3-Phe4-dap5-Leu6)cyclo(2
-5)(MEN10701) (dap: (2R)-2,3-diaminopropionic acid). This compound is an analogue ofcyclo(Met1-Asp2-Trp3-Phe4-Dap5-Leu6)cyclo(2-5) (MEN10627) (Dap: (2S)-2,3-diaminopropionic acid),which is the most potent and selective, peptide-based NK2 receptor antagonist known to date. MEN10701differs from MEN10627 for the D chirality oftheAsp2 and Dap5 residues; it was designed tobetter understand the role of the lactame bridge in determiningtheshape of the molecule and to elucidate whether its position, above orbelow the plane containing thepharmacophores (Met1, Trp3, Phe4,and Leu6 side chains), could modulate the biologicalresponse. Despiteour expectations, the uncoercible bicyclic structure of MEN10627 isdramatically coerced into a novelconformation, by the replacement of the lactame bridge forming units(Asp2 and Dap5) with residues ofoppositechirality. The overall shape of MEN10701 is also quite uniquebecause of its compactness. It is ellipsoidalinstead of being rectangle-like, and the structure is stabilized by twointramolecular hydrogen bondsencompassing two type I' -turns. This structure can be added tothe repertoire of rigid -turn scaffolds forthe design of bioactive molecules, which require turned motifs toelicit potency and specificity.
-5)(MEN10701) (dap: (2R)-2,3-diaminopropionic acid). This compound is an analogue ofcyclo(Met1-Asp2-Trp3-Phe4-Dap5-Leu6)cyclo(2-5) (MEN10627) (Dap: (2S)-2,3-diaminopropionic acid),which is the most potent and selective, peptide-based NK2 receptor antagonist known to date. MEN10701differs from MEN10627 for the D chirality oftheAsp2 and Dap5 residues; it was designed tobetter understand the role of the lactame bridge in determiningtheshape of the molecule and to elucidate whether its position, above orbelow the plane containing thepharmacophores (Met1, Trp3, Phe4,and Leu6 side chains), could modulate the biologicalresponse. Despiteour expectations, the uncoercible bicyclic structure of MEN10627 isdramatically coerced into a novelconformation, by the replacement of the lactame bridge forming units(Asp2 and Dap5) with residues ofoppositechirality. The overall shape of MEN10701 is also quite uniquebecause of its compactness. It is ellipsoidalinstead of being rectangle-like, and the structure is stabilized by twointramolecular hydrogen bondsencompassing two type I' -turns. This structure can be added tothe repertoire of rigid -turn scaffolds forthe design of bioactive molecules, which require turned motifs toelicit potency and specificity.