Discovery and Characterization of Y4R Allosteric Modulators Using Computer-Aided Drug Design

Abstract

The human neuropeptide Y (NPY) receptor family (Y1R, Y2R, Y4R, and Y5R) are comprised of G-protein coupled receptors (GPCR) that bind the ligands neuropeptide Y (NPY), polypeptide YY (PYY), and pancreatic polypeptide (PP). Those have been shown to play critical roles in regulating satisfaction after food in-take and energy homeostasis. Since Y4 is the only NPY receptor with much higher affinity towards PP than to other two peptide ligands, selective agonists of Y4 could be potentially used in obesity treatment. Computer-aided drug discovery/design (CADD) has been universally used to facilitate and expedite the development of small molecule-based therapeutics. Ligand-based virtual screening can save time and resources by quickly narrowing libraries of millions drug-like molecules to hundreds of compounds candidates for experimental tests and validation. On the other hand, structure-based methods such as ligand docking help characterize the interaction be-tween ligands and target proteins when the crystal structures are not available. The overall focus of this dissertation was to design and validate methods for the computational modeling of ligands in complex with G protein-coupled receptors (GPCRs) and apply the methods to the modeling of allosteric modulators for the neuropeptide Y 4 receptor (Y4R).