A NOVEL RIGID BETA-TURN MOLECULAR SCAFFOLD

We describe here the solution H-1 NMR analysis, restrained and unrestr ained molecular dynamic simulations of the bicyclic peptide cyclo(Met( 1) -asp(2)-Trp(3)-Phe(4)-dap(5)-Leu(6))cyclo(2 beta-5 beta) (MEN10701) (dap: (2R)-2,3-diaminopropionic acid). This compound is an analogue o f cyclo(Met(1) -Asp(2)-Trp(3)-Phe(4)-Dap(5)-Leu(6))cyclo(2 beta-5 beta ) (MEN10627) (Dap: (2S)-2,3-diaminopmpionic acid), which is the most p otent and selective, peptide-based NK2 receptor antagonist known to da te. MEN10701 differs from MEN10627 for the D chirality of the Asp(2) a nd Dap(5) residues; it was designed to better understand the role of t he lactame bridge in determining the shape of the molecule and to eluc idate whether its position, above or below the plane containing the ph armacophores (Met(1), Trp(3), Phe(4), and Leu(6) side chains), could m odulate the biological response. Despite our expectations, the uncoerc ible bicyclic structure of MEN10627 is dramatically coerced into a nov el conformation, by the replacement of the lactame bridge forming unit s (Asp(2) and Dap(5)) 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' beta-turns. This structure can be added to the repertoire of rigid beta-turn scaffolds for the design of bioactive molecules, which requi re turned motifs to elicit potency and specificity.