CONFORMATIONAL STUDIES ON MODEL DIPEPTIDES OF GLY, L-ALA AND THEIR C-ALPHA-SUBSTITUTED ANALOGS

As a part of the development of conformational guidelines for the desi gn of metabolically altered peptidomimetics, we present conformational energy calculations on model dipeptide compounds with glycine (Gly), L-alanine (Ala), alpha-aminoisobutyric acid (Aib), L-tert-butylglycine (Tie), L-phenylglycine (Phg), (alpha,alpha)-diphenylglycine (D phi g) , L-2-aminobutyric acid (Abu), 2-amino-2-ethylbutyric acid (Deg), L-2- amino-2-vinylacetic acid (Ava) and (alpha,alpha)divinylglycine (Dvg). The energy calculations have been made using molecular mechanics metho ds with a force field derived from MM2. The salient features are expre ssed in terms of conformational energy plots, drawn as a function of t he backbone torsion angles phi(C'(i-1)-N-i-C-i(alpha)-C'(i)) and psi(N -i-C-i(alpha)-C'-N-i+1). The low-energy structures of these compounds are qualitatively consistent with the X-ray crystal structure analyses of peptides and peptidomimetics. They are also in agreement with the results of the solution-phase studies carried out by NMR and IR techni ques. The results obtained have important implications in the design o f conformationally restricted peptidomimetics. (C) Munksgaard 1995.