Page - (000302) - in Biomedical Chemistry: Current Trends and Developments

the peptide is not completely rigid (e.g., using side chain cyclizations as constraints) and therefore several differently constrained analogues of the peptide may be required in order to derive a putative receptor-bound conformation. When peptides bind to their receptors they become an integral part of the protein structure and thus can be predicted to adopt secondary structure motifs as part of the bioactive conformation (Hruby, 2002). Therefore, conformational constraints or organic scaffolds that induce or mimic secondary structures can give valuable information when searching for the bioactive conformation and may provide a valuable starting point for the development of peptidomimetic drugs. 3.3.1.1.3.1 Secondary Structure Mimetics The main secondary structures found in proteins and peptides are the α- helix, β-sheet and turns. For peptide ligands, secondary structures correspond to local rigidified structure motifs with a specific arrangement of the residue side chains, which could provide important recognition elements during receptor binding and activation (Rose, 1985). Thus, mimicking such structural elements of the peptide with organic scaffolds is a rational approach in the development of peptidomimetic compounds. In addition, such an approach may also give compounds with increased metabolic stability and higher receptor specificity, and provide a rational basis for exploring the conformational effect on activity (Hruby, 1982). There are indications that turn structures are present in several peptide ligands when bound to their receptors, and this makes it appealing to mimic turns (Rose, 1985). The major types of turns present in proteins and peptides are the β-turn and the γ-turn, depicted in Fig. 3.3.5, where turn mimetic examples also can be found. Venkatachalam first suggested the presence of β-turns in proteins based on modeling studies in 1968 (Venkatachalam, 1968). The β-turn causes reversal of the peptide backbone and is defined as a sequence of four amino acid residues in a non-helical segment with a distance of less than 7 Å between C α ,i and C α,i+3 (Lewis, 1973). The β-turns are often, but not necessarily, stabilized by a COi–NHi+3 hydrogen bond. The β-turn has been divided into several types, depending on the values of the