MOLECULAR MECHANICS STUDIES ON CONFORMATIONALLY RESTRICTED DIPEPTIDE MODELS - TYLAMINO-N-METHYL-2,5-CYCLOHEXADIENE-1-CARBOXAMIDE AND ITS DERIVATIVES

We present conformation energy calculations on the model dipeptide 1-a cetylamino-N-methyl-2,5-cyclohexadiene-1 -carboxamide (1) and its two derivatives in which the C-2 and C-6 of the cyclohexadiene ring are su bstituted. The energy calculations have been done using molecular mech anics methods with a force field derived from MM2. The salient feature s are expressed in terms of conformational energy plots, drawn as a fu nction of the backbone torsion angles phi(C-N-C-alpha-C) and psi(N-C-a lpha-C-N). Two families of conformations are found to be the global mi nima in the (phi psi) space, one corresponding to a region with fully extended structures characterized by (phi psi) = (180 degrees +/- 20 d egrees 180 degrees +/- 20 degrees) and the other characterized by (phi psi) = (180 degrees +/- 20 degrees, +/- 60 +/- 20 degrees). The low e nergy structures of these model compounds are qualitatively consistent with the available amount of X-ray crystal structure data on peptido- mimetics similar to 1. The salient results obtained have important imp lications on the design of constrained peptidomimetics with the above two conformations. (C) 1995 Academic Press, Inc.