Identifying Pharmacophore Elements

Identifying the pharmacophore elements plays a crucial role to develop a potent and optimized design of peptides. (1) "Truncating" one amino acid at a time from the amino and/or carboxy termini can lead to a minimum active fragment or sequence responsible for biological activity. (2) "Amino acid scans" can reveal the binding affinities and activities of a primary ligand. These scans help to deduce the importance of the side chain groups required for biological activity that is responsible for molecular recognition and signal transduction. Amino acid scans in peptide or protein design include the following. (a) Alanine scans: For a given peptide each amino acid is replaced by an L-alanine to evaluate the relative significance of the side chain group in the binding and biological activity of the peptide. (b) D-Amino acid scans: Each L-amino acid is replaced by its corresponding D-amino acid. Advantages of D-amino acid offer the stability of certain reverse (hairpin) turns or destabilization of a-helices, thus providing insights about the chirality of the amino acids in the interested peptide sequence. "D-alanine scans" offer the dual-advantage of the aforementioned two scans thus disclosing the crucial role of chirality and side chain group at the same time. (c) Proline scans: Replacing a given amino acid by proline, or other ^-alkylated amino acids provide specific insights into the importance of backbone conformations. Many GPCRs recognize P-turn structural type of ligands and a judicious replacement by proline can, for example, induce turns and give rise to conformers that may be crucial toward design of a ligand. (d) Bulky amino acid scans: Bulky amino acids and aromatic amino acids can play important roles in peptide ligand binding with receptors/ acceptors because of their size or hydrophobicity. Often bulky amino acids will cause hindrance of binding of the peptide to the receptor/acceptor binding site, or they can show vast differences in binding to one receptor subtype over another to enhance selectivity for a particular receptor subtype. (3) Cyclic scans: As discussed earlier in the global restriction section, side-chain-to-side-chain, side-chain-to-backbone, C-terminal-to-N-terminal, backbone-to-backbone, and other combinations are employed to stabilize or favor segments of the peptide to adopt a global conformation. Varying types of cyclized moieties and ring sizes are adapted to explore functional and biological changes. Cyclization of peptides is often used to bias the peptide a-helix, P-turn, and other hairpin type conformations that may be crucial for the biological activity. (4) Other scans: Amide bond replacement scans and aza scans (aza peptides adopt P-turn conformations) are additional methods used for the design of peptides or peptidomimetics.

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