Neuropeptide Y (NPY) has been implicated in a variety of pathological conditions including; cardiovascular and respiratory abnormalities, mental depression, Parkinson's and Alzheimer's disease. A structure-based drug design program to develop NPY peptidomimetics for intervention in these disorders would be facilitated by a structural model of the NPY binding site. The generation of such a model in turn requires an understanding of the molecular interactions between NPY peptide ligands and their receptor subtypes. In Phase I we have generated and tested an interactive 3-dimensional molecular model of the Y1 receptor system. A multidisciplinary effort in computational chemistry, molecular biology and pharmacology has helped define the structural requirements for ligand binding. Our structural explorations of the NPY receptor system will be expanded in Phase II and will result in an experimentally validated model of the binding site that should support the design of highly selective NPY peptidomimetic drugs targeting specific pathologies.
