Most hormones and neurotransmitters in human beings and related animals are peptides and most of them have a high degree of conformational flexibility. This is advantageous physiologically because these molecules have to adopt different conformations during their biological lifetimes. However, this causes problems for the design of drugs related to these compounds for their receptors, especially since the receptors for these ligands are membrane receptors, and thus far it has not been possible to get X-ray crystal structures of peptide-receptor complexes. Thus, ligand-based strategies have been developed based on conformation constraints of backbone conformation (phi-psi space) and/or topographical constraint (chi space) of side chain conformations. Both approaches will be used to illustrate the relationship between conformation and topography to biological activity properties. Effects on potency, receptor subtype selectivity and efficacy will be discussed.
Supported by grants from the U.S. Public Health Service, National Institutes of Health