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.
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.
|Korczynska, Magdalena; Clark, Mary J; Valant, Celine et al. (2018) Structure-based discovery of selective positive allosteric modulators of antagonists for the M2 muscarinic acetylcholine receptor. Proc Natl Acad Sci U S A 115:E2419-E2428|
|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|
|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|
|Liu, Xiangyu; Ahn, Seungkirl; Kahsai, Alem W et al. (2017) Mechanism of intracellular allosteric ?2AR antagonist revealed by X-ray crystal structure. Nature 548:480-484|
|Fish, Inbar; Stößel, Anne; Eitel, Katrin et al. (2017) Structure-Based Design and Discovery of New M2 Receptor Agonists. J Med Chem 60:9239-9250|
|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|
|Kruse, Andrew C; Hu, Jianxin; Kobilka, Brian K et al. (2014) Muscarinic acetylcholine receptor X-ray structures: potential implications for drug development. Curr Opin Pharmacol 16:24-30|
Showing the most recent 10 out of 15 publications