Page - (000300) - in Biomedical Chemistry: Current Trends and Developments

the importance of amino acid side chains by systematically replacing each residue within the peptide with alanine, glycine or the corresponding d-amino acid. Alanine and glycine are the smallest amino acids available, having a methyl and a hydrogen side chain, respectively. Thus, they should have only a small impact on the overall binding affinity, unless they substitute a crucial amino acid in the original peptide. N- or C-terminal truncation removing one amino acid at a time provides information about the minimal sequence needed for biological activity. The importance of a basic N-terminal or an acidic C- terminal is determined by the introduction of capping groups. These initial investigations will lead to the identification of the essential residues in the peptide and potential pharmacophoric groups, i.e. structural features that are required for the biological activity. Based on the information gained from these studies, further structural modifications are undertaken to improve stability, potency and selectivity. 3.3.1.1.3 Bioactive Conformation One of the central steps in peptidomimetic design is to elucidate the bioactive conformation of the peptide, i.e. the conformation adopted when it is bound to the macromolecular target. Conformational restrictions are frequently used to explore the bioactive conformation and to enhance bioavailability by improving enzymatic stability, (Grauer, 2009; Veber, 1985). A constraint that leads to a reduction in the loss of conformational entropy upon interaction with the target can also increase the binding affinity (Rizo, 1992). Global and local constraints can be achieved by cyclization (Hruby, 2002), N-methylation (Rizo, 1992), isosteric substitution (Rizo, 1992; Sewald, 2002) or by secondary structure replacement (which will be discussed in more detail below) (Kim, 2000) as exemplified in Fig. 3.3.4.