The overall goal of this proposal it to develop structure-based approaches to discover new G protein coupled receptor (GPCR) ligands having new signaling properties and specificities. GPCRs are involved in regulating virtually every aspect of physiology and are pivotal targets for drug discovery. Until now, ligand discovery efforts for GPCR has been empirically driven, and though this has had successes, it has restricted the field to sites precedented by canonical, often natural ligands. Considering the remarkable progress in identifying new GPCRs over the past two decades, drug discovery for this family of receptors using classical approaches has been disappointing. Most available ligands act at orthosteric sites, competing directly with the natural hormones and neurotransmitters. In the rare circumstances that they bind allosterically, their discovery has been fortuitous, their optimization difficult, as has been the dissection of their signaling. The recent efflorescence of GPCR X-ray structures was followed by the application ligand docking methods demonstrating the feasibility of this approach for the discovery of novel orthosteric ligand chemotypes for several GPCRs. We propose an integrated program of structure-based exploitation of GPCRs for new ligand chemotypes with an emphasis on allosteric ligands, their testing for new signaling properties, the determination of their structures bound to their GPCRs, and their optimization for affinity and signaling. This proposal builds on a network of existing collaborations among the labs of Kobilka, Shoichet, Sunahara and Gmeiner over the past four years. These four investigators bring together a unique combination of expertise in GPCR structural biology, ligand docking, GPCR pharmacology and function, and medicinal chemistry. Preliminary studies from this group demonstrate the feasibility and potential value of this approach.

Public Health Relevance

This Program Project will develop new approaches to develop more selective and effective drugs for GPCRs, which are the largest family of membrane proteins in the human genome. Drugs acting on GPCRs can have an impact on a broad spectrum of diseases including: cardiovascular disease, pulmonary disease, inflammation, diabetes and obesity, behavioral disorders and Alzheimer's disease.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Program--Cooperative Agreements (U19)
Project #
Application #
Study Section
Special Emphasis Panel (ZRG1-BST-J (40))
Program Officer
Dunsmore, Sarah
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Stanford University
Schools of Medicine
United States
Zip Code
Brea, Roberto J; Cole, Christian M; Lyda, Brent R et al. (2017) In Situ Reconstitution of the Adenosine A2A Receptor in Spontaneously Formed Synthetic Liposomes. J Am Chem Soc 139:3607-3610
Stößel, Anne; Brox, Regine; Purkayastha, Nirupam et al. (2017) Development of molecular tools based on the dopamine D3 receptor ligand FAUC 329 showing inhibiting effects on drug and food maintained behavior. Bioorg Med Chem 25:3491-3499
Manglik, Aashish; Lin, Henry; Aryal, Dipendra K et al. (2016) Structure-based discovery of opioid analgesics with reduced side effects. Nature 537:185-190
DeVree, Brian T; Mahoney, Jacob P; Vélez-Ruiz, Gisselle A et al. (2016) Allosteric coupling from G protein to the agonist-binding pocket in GPCRs. Nature 535:182-6
Thal, David M; Sun, Bingfa; Feng, Dan et al. (2016) Crystal structures of the M1 and M4 muscarinic acetylcholine receptors. Nature 531:335-40
Mahoney, Jacob P; Sunahara, Roger K (2016) Mechanistic insights into GPCR-G protein interactions. Curr Opin Struct Biol 41:247-254
Thorsen, Thor Seneca; Matt, Rachel; Weis, William I et al. (2014) Modified T4 Lysozyme Fusion Proteins Facilitate G Protein-Coupled Receptor Crystallogenesis. Structure 22:1657-64
Kruse, Andrew C; Li, Jianhua; Hu, Jianxin et al. (2014) Novel insights into M3 muscarinic acetylcholine receptor physiology and structure. J Mol Neurosci 53:316-23
Kruse, Andrew C; Kobilka, Brian K; Gautam, Dinesh et al. (2014) Muscarinic acetylcholine receptors: novel opportunities for drug development. Nat Rev Drug Discov 13:549-60
Kruse, Andrew C; Weiss, Dahlia R; Rossi, Mario et al. (2013) Muscarinic receptors as model targets and antitargets for structure-based ligand discovery. Mol Pharmacol 84:528-40

Showing the most recent 10 out of 11 publications