A Novel Rigid β-Turn Molecular Scaffold

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