Datorbaserade studier av ortosterisk, allosterisk, och indirekt allosterisk modulering av adenosinreceptorer

Tidsperiod: 2018-01-01 till 2021-12-31

Projektledare: Jens Carlsson

Finansiär: Vetenskapsrådet

Bidragstyp: Projektbidrag

Budget: 3 200 000 SEK

The project is focused on structure-based strategies for discovery of selective ligands of G protein-coupled receptors (GPCRs) and understanding of GPCR dimerization. The A1 adenosine receptor (A1R) is receiving increasing attention as a therapeutic target, but drug discovery has been hampered by off-target interactions, in particular with the A2AR. The recent determination of crystal structures for the A1R and A2AR provides a unique opportunity for rational design of selective ligands. Four million commercially available compounds will be screened against orthosteric and allosteric sites using molecular docking to identify selective A1R leads. Top-ranked compounds with predicted selectivity will be evaluated experimentally. The second project focuses on GPCR dimerization. The A1R and A2AR form homodimers and also interact with D1 and D2 dopamine receptors (D1R and D2R) in the brain. For this reason, GPCR dimers represent therapeutic targets for drug development against CNS disorders. However, understanding of the structural basis of dimerization and allosteric modulation is limited. We will develop a combined modeling and experimental technique to generate atomic resolution models of A1R-A1R, A2AR-A2AR, A1R-D1R, and A2AR-D2R complexes with the goal to understand the structural basis and specificity of homo- and heteromerization. Predictions based on our models will be tested experimentally, which will shed light on how dimerization modulates GPCR signaling.