Abstract
Proteins and peptides are known to interact with macromolecular receptors to trigger biological processes. In order to interrupt these processes, medicinal chemists have developed antagonists which block the native ligand from binding to its receptor. A rational design of such antagonists is facilitated by our understanding based on the spectacular advances made by molecular biology. This has helped us in identifying the region of protein and its conformation that interacts with the native ligand. The remarkable progress in the field of molecular biology, peptide synthesis, and molecular modelling has dramatically increased understanding of the relationship between protein and peptide structure and their biological function. The recent progress in the synthesis and screening of huge peptide libraries has focused attention on small peptides as important lead structures for the development of potential therapeutic agents. The linear peptide fragments are flexible and exhibit numerous conformations in solution and even in the solid state. However, if one can restrict the conformational freedom of these linear peptides by introducing some constraints in the structure, their solution conformations can be determined by usual physical methods. The conformational restriction can help render a biologically active peptide more potent, more specific and orally active and this may give rise to species which are therapeutically useful. Such constrained structures will also shed useful information on the receptor bound conformation of the ligand. This conformational knowledge about ligands which retain affinity for receptors is then used to develop a model for the biologically active conformation of peptide antagonist, i.e., an antagonist pharmacophore. A number of X-ray structures of proteases with their corresponding peptide inhibitors show that local regions of peptides bound to active site adopt an extended conformation very similar to a protein beta sheet or beta strand. The antibody-antigen complexes also show binding of the peptide antigens in a beta turn conformation. The importance of this information for drug design is that the design of the antagonist pharmacophore may be based on a particular protein structural motif. An important structural feature of many biologically active peptides and proteins is the beta turn motif. These turns are often situated at the protein surface and usually consist of polar residues that offer the opportunity of intermolecular interactions with other protein surfaces and hence provide site for intermolecular recognition. The importance of beta turns in peptides and proteins may well be crucial in receptor interactions that ultimately lead to biological activity.
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© 1999 Springer Science+Business Media New York
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Iqbal, J., Nandy, J.P., Prabhakaran, E.N., Rajesh, S., Krishnan, S. (1999). Cobalt Catalysed Synthesis of-β-Turn Mimics as Model for the Bioactive Conformation of HIV-1 Protease Inhibitors. In: Scolastico, C., Nicotra, F. (eds) Current Trends in Organic Synthesis. Springer, Boston, MA. https://doi.org/10.1007/978-1-4615-4801-0_42
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DOI: https://doi.org/10.1007/978-1-4615-4801-0_42
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