Our long term goal is to leverage GPCR structures to discover new chemotypes, and use these to as leads and probes to disentangle signaling pathways. Libraries of over 4.4 Million commercially available molecules are docked against GPCRs, typically targeting allosteric sites, and those that rank well by a physics-based complementarity score are acquired for testing. Those that are confirmed are optimized for affinity, specificity, and permeability. We begin relatively conservatively, seeking ligands with new chemotypes and physical properties for the orthosteric site of muscarinic receptors, and build on this to target the allosteric sites newly revealed in the structures.
The specific aims are: 1. Novel chemotypes for the orthosteric sites ofthe muscarinic receptors. We are particularly focused on chemotypes with new physical properties (e.g., uncharged ligands) and sub-type specificities. 2. Ligands to the Gs-binding site ofthe B2-AR. Combined with an orthosteric ligand, and potentially on their own, molecules that bind to this site will bias signaling down non-G-protein pathways, such as that of arrestin. 3. Allosteric ligands ofthe muscarinic receptor. The high sequence identity in the orthosteric site ofthe five muscarinic subtypes has interfered with the discovery of specific ligands. Sequence is much less conserved in the allosteric sites revealed in the new structures, and we are targeting these for sub-type specific ligands. 4. Dimer-site ligands for the u-opioid receptor. Molecules that bind to this site will stabilize dimer vs. momomer signaling, suggesting a new route to specificity among opioid receptors and new tools to investigate the role of oligomers in GPCR signaling. Whereas these goals are ambitious, extensive preliminary results, in collaboration with the Kobilka and the Sunahara labs, support their feasibility.
GPCRs are the most common targets of therapeutic drugs. Most of these drugs owe to empirical screening, and until very recently it has been impossible to target drug-candidates to specific sites, with specific impacts on physiology and signaling. With the advent ofthe new GPCR structures, this is now possible-this project seeks to exploit this opportunity by discovering molecules that target GPCRs in entirely new ways.
|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|
|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|
|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|
|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