Conformational studies on model peptides with 1-aminocyclobutane 1-carboxylic acid residues.

Abstract

Conformationally constrained peptidomimetics are being increasingly used in the development of 3-D pharmacophores of peptide-based drug candidates and to alter their metabolic stability towards achievements of oral bioavailability. Here we present conformational energy calculations on model compounds containing 1-aminocyclobutane carboxylic acid (ACBC) and its derivatives using molecular mechanics methods. The low-energy models adopt conformations characteristic of a variety of regular structures such as the alpha-helix, 3(10)-helix, gamma-turn and polyproline-II-type three- and fourfold helices. The energetically most favored models adopt the gamma-turn (2.2(7) helix) conformation or alpha-/3(10)-helical conformation, both of either handedness, depending on the substituents on the cyclobutane. These results are qualitatively consistent with the crystal structures of peptide analogs containing ACBC and have implications for the design of peptidomimetics.