Design of nonpeptides from peptide ligands for peptide receptors

To develop nonpeptide ligands, efforts are in progress to develop templates and aspects of conformational design that permit assembling of all components necessary for molecular recognition and transduction. The proper choice of template that can place the key side chain residue in 3D space is still difficult, and thus only partial success has been achieved in terms of potent and selective ligands. Nonpeptide design is a highly multidisciplinary area that often relies on (1) new asymmetric synthesis and methodologies for the preparation of novel molecules, (2) high-throughput screening of ligands and libraries of ligands using multiple in vitro and in vivo biological assays, (3) computational methods, and (4) state-of-the-art biophysical methods for determining structural, conformational, topographical, and dynamic properties of designed ligands. Studies since the early 1980s have demonstrated that agonists and antagonists have different structure–activity relationships. There still is no universal approach to develop antagonists from agonists for peptide hormones and neurotransmitters, but once a lead has been obtained, there are general approaches that can be used to further develop antagonists.