G-Protein Coupled Receptors (GPCRs) represent both the largest class of signaling receptors in the human genome and the family most targeted by therapeutic drugs. Responding to ligands that vary from protons to bioamines to lipids to chemokines, their attractiveness for drug discovery reflects the importance of the signals they transduce and, as has become apparent with the determination of their structures, the intrinsic ligand- ability of their binding sites. Despite intense interest, most GPCRs remain sparsely annotated by chemical matter. In this grant we will take a two-pronged approach to overcome these difficulties.
In Specific Aim 1 we will develop and validate scalable assays in yeast and mammalian cells with which to screen a library of 5321 drugs and reagents.
In Specific Aim 2 we will develop and validate scalable computational screens against modeled structures of the orphan GPCRs, leveraging the empirical hits. By the end of the project period we anticipate validating and executing physical screens against 30 orphan GPCRs and producing computationally optimized lead-like compounds for 20.

Public Health Relevance

G protein coupled receptors represent the single largest class of human proteins targeted by approved medications. There are at least 380 GPCRs in the human genome, although therapeutic drugs are available for only a small number of them. In this grant we will develop new tools to identify which of the relatively understudied G protein coupled receptors might represent new targets for therapeutic drug development.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
Research Project--Cooperative Agreements (U01)
Project #
Application #
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Yao, Yong
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of North Carolina Chapel Hill
Schools of Medicine
Chapel Hill
United States
Zip Code
Oprea, Tudor I; Bologa, Cristian G; Brunak, Søren et al. (2018) Unexplored therapeutic opportunities in the human genome. Nat Rev Drug Discov 17:317-332
Pera, Tonio; Deshpande, Deepak A; Ippolito, Michael et al. (2018) Biased signaling of the proton-sensing receptor OGR1 by benzodiazepines. FASEB J 32:862-874
Wacker, Daniel; Stevens, Raymond C; Roth, Bryan L (2017) How Ligands Illuminate GPCR Molecular Pharmacology. Cell 170:414-427
Lansu, Katherine; Karpiak, Joel; Liu, Jing et al. (2017) In silico design of novel probes for the atypical opioid receptor MRGPRX2. Nat Chem Biol 13:529-536
Roth, Bryan L; Irwin, John J; Shoichet, Brian K (2017) Discovery of new GPCR ligands to illuminate new biology. Nat Chem Biol 13:1143-1151
Wang, Sheng; Wacker, Daniel; Levit, Anat et al. (2017) D4 dopamine receptor high-resolution structures enable the discovery of selective agonists. Science 358:381-386
Manglik, Aashish; Lin, Henry; Aryal, Dipendra K et al. (2016) Structure-based discovery of opioid analgesics with reduced side effects. Nature 537:185-190
Sato, Seiji; Huang, Xi-Ping; Kroeze, Wesley K et al. (2016) Discovery and Characterization of Novel GPR39 Agonists Allosterically Modulated by Zinc. Mol Pharmacol 90:726-737
Farrell, Martilias S; McCorvy, John D; Huang, Xi-Ping et al. (2016) In Vitro and In Vivo Characterization of the Alkaloid Nuciferine. PLoS One 11:e0150602
Zhu, Hu; Aryal, Dipendra K; Olsen, Reid H J et al. (2016) Cre-dependent DREADD (Designer Receptors Exclusively Activated by Designer Drugs) mice. Genesis 54:439-46

Showing the most recent 10 out of 16 publications