The proposed research will apply comparative modeling and ligand discovery by molecular docking to the approximately 100 out of 350 non-olfactory G-protein coupled receptors (GPCRs) for which endogenous ligands are not known. GPCRs are compelling drug targets due to their central position in cellular signaling; as a class, they are capable of binding extremely chemically diverse ligands ranging from protons and metal ions to small molecules and lipids to peptides hormones and even folded globular proteins. Despite this diversity, GPCRs share a conserved mechanism of action by which characteristic conformational changes transduce information across the cell membrane to activate intracellular signaling pathways. GPCR extracellular binding sites are known for being highly druggable-that is, receptive to interactions by exogenous small molecules-and in fact they represent the protein targets of between 30% and 50% of drugs currently on the market. The so-called orphan GPCRs, with no annotated endogenous ligands, therefore represent a rich source of novel mechanisms of action for future drug development. Historically, GPCRs have been This project will begin by leveraging experimentally identified ligands of representative orphan GPCRs to perform virtual screening on a large compound database using a methodology already shown to result in high hit rates. Next, the results of this initial phase wil be used to refine and automate the methodology to construct an integrated modeling and docking pipeline that could be applied across the orphan GPCRome. Additionally, chemoinformatics, docking, and protein-protein interface analysis will be used with the goal of identifying not only surrogate ligands useful as tool compounds, but also the endogenous ligands of each GPCR and their role in the metabolome.