P-Turn structures are an important class of peptides and are recognized by many GPCR's for their affinity and potency. Besides the aforementioned strategies of globally restricting dynamics of a peptide, enhancing P-turns also provides an excellent opportunity for design of novel bicyclic conformations. A P-turn can be viewed as a 10-membered ring formed from four amino acids that are stabilized by a hydrogen bond between the carbonyl group of the first amino acid residue and the amine-hydrogen of the fourth amino acid residue. When such interactions are stabilized by inducing greater constraints on the second and third amino residues can lead to novel templates for P-turn peptidomimetics.
The development of peptide mimetics can be a critical drug discovery strategy. The evolution of peptide ligands to small molecule mimetics has been a major goal in the field, with several notable successes. Peptides are ideal drug leads, but often their stability to proteolytic enzymes and their bioavailability need to be enhanced. This can be done by incorporating various computational tools for molecular design, proprietary scaffolds, conformational constraints, conformation-activity analysis, and lead optimization strategies to design mimetics that will retain the desired biological properties of the peptide lead, but are metabolically stable, have appropriate diversity, and can be tailored to have desired drug-like pharmaceutical properties. The peptide mimetic design strategies are summarized in Figure 8.8. The interaction of a peptide with a receptor/acceptor may occur via a direct binding of a linear sequence of the peptide in one of the conformations accessible to a particular peptide. Linear peptides are the mode of recognition of many peptide ligands for receptors/ acceptors. In other cases, turn structures or cyclic structures are important, as in MTII, where the -His-D-Phe-Arg-Trp- peptide sequence is oriented in a turn motif. In larger peptides or proteins, the folding of the peptide may bring groups that are distant in a sequence into close spatial arrangements, and thus the "binding motif" is a 3D arrangement of the peptide side chain groups involved in recognition. In other cases, the recognition may be along a face of a P sheet or a helical sequence. The linear, folded, and 3D presentations can all be translated from peptides to peptide mimetics.
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