Design criteria for molecular mimics of fragments of the beta-turn. 1. C alpha atom analysis.

Abstract

Peptides represent an extensive class of biologically active molecules. They may be used as leads in the development of novel therapeutic agents provided the pharmacophoric information present within them can be translated into non-peptide analogs that lack the peptide backbone and are stable to proteolysis. This is the rationale for peptidomimetic drug design. Frequently, the beta-turn has been implicated as a conformation important for biological recognition of peptides. Empirical evidence from known peptidomimetics, coupled with a theoretical model of peptide binding and the observation that glycine and proline residues are common within the beta-turn, has suggested the design of molecules to mimic placement of between two and four of the side-chains. The moderate number of different beta-turn conformations, combined with the combinatoric nature of side-chain selection complicates the procedure. In this paper, cluster analysis has been used to classify the arrangement of C alpha atoms about the various fragments of the beta-turn. Recombination of the observed patterns provides a general model for the beta-turn which may be used as an effective screen for potential peptidomimetic scaffolds in chemical databases.