CONFORMATIONAL-ANALYSIS OF DIPEPTIDE MIMETICS

A compendium of compounds designed as dipeptide mimetics was collected from the literature. Conformational space available to these molecule s was evaluated to obtain distance and torsion angle parameters to aid in selection of mimetics for specific target peptides or to explore d iversity strategies. Conformations were searched using the RandomSearc h algorithm in SYBYL. Data were collected for conformations of each mo lecule falling within 5 kcal/mol of the minimum. The distance between capping groups on the N- and C-termini of the molecules was measured a s well as the pseudotorsion angle about a virtual bond between these t wo points. Molecules are classified based on the torsion angle space o ccupied and range of distances spanned by the resulting conformations. A large percentage of the dipeptide mimetics studies here have redund ant conformational properties. The distribution of distances for all m olecules covers an overall range of 3-15 Angstrom, the majority fallin g between 5-8 Angstrom. The angles for the majority of the molecules c over a wide range of torsional space with essentially no gaps in the v alues they can occupy, although these molecules can be subdivided by t he average distance spanned by the allowed conformations. A smaller gr oup of molecules have torsion angles that are restricted to a range of +/-60 degrees about the cis position (0 degrees). Representative exam ples of each group are shown. We conclude that despite the significant effort to devise unique molecular structures as dipeptide mimetics, t here is a need for more conformationally restricted compounds to mimic specific peptide conformations, and to complement molecular diversity strategies. (C) 1997 John Wiley & Sons, Inc.