Page - (000301) - in Biomedical Chemistry: Current Trends and Developments

Figure 3.3.4: A) Cyclization strategies that can be performed in a peptide sequence to introduce global constraints (Rizo & Gierasch, 1992). B) Positions in a peptide that can be methylated. Methylation of both the backbone atoms and the side chains can introduce local constraints (Rizo, 1992). C) Isosteric replacement of the peptide bond can introduce local constraints. It should be noted that such replacements are not always real constraints, but alter the overall conformational behavior of the peptide backbone to varying degrees. In some cases the flexibility is increased (Rizo, 1992; Sewald, 2002). D) Secondary structure mimetics can induce a desired conformation when introduced into the peptide backbone (Rosenström, 2006; Schmidt, 1998; Sewald, 2002). Many high-quality 3D structures of ligands, when bound to their macromolecular target, have been obtained using X-ray crystallography. However, this technique is not readily applicable to all types of systems. For example, enzymes have been easier to crystalize as compared to membrane bound G-protein coupled receptors (GPCRs), although the number of crystalized receptors are increasing. To model the receptor- bound conformation when the 3D structure of the target is unknown, ligand-based experimental or theoretical studies have to be performed. Conformations adopted by flexible linear peptides are numerous, and are strongly influenced by interactions with the environment (Rose, 1985). Therefore, to limit the conformational flexibility, conformational constraints can be introduced into the peptide to provide information about the bioactive conformation. In many cases the constrained part of