CANNABIDIM
Molecular modelling of the cannabinoid CB1 receptor homodimer and its interaction with ligands: the role of membrane cholesterol and the CRIP1a protein
| Coordinatore | Itä-Suomen yliopisto
Organization address
address: YLIOPISTONRANTA 1 E contact info |
| Nazionalità Coordinatore | Finland [FI] |
| Totale costo | 272˙231 € |
| EC contributo | 272˙231 € |
| Programma | FP7-PEOPLE
Specific programme "People" implementing the Seventh Framework Programme of the European Community for research, technological development and demonstration activities (2007 to 2013) |
| Code Call | FP7-PEOPLE-2011-IEF |
| Funding Scheme | MC-IEF |
| Anno di inizio | 2012 |
| Periodo (anno-mese-giorno) | 2012-08-01 - 2014-07-31 |
Partecipanti
| # | ||||
|---|---|---|---|---|
| 1 |
Nome Ente NON disponibile
Organization address
address: YLIOPISTONRANTA 1 E contact info |
FI (Kuopio) | coordinator | 272˙231.80 |
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Obiettivo del progetto (Objective)
'The cannabinoid CB1 receptor (CB1R) is an attractive molecular target for the treatment of substance abuse, drug addiction, schizophrenia, bipolar disorder, motor dysfunction including Huntington’s disease, as well as cardiometabolic disease and metabolic syndrome. The general aim of the project is to investigate in silico the phenomenon of the homodimerization of the CB1R, the interaction of the CB1R homodimer with ligands, and to study the effect of membrane cholesterol and the cannabinoid receptor interacting protein 1a, CRIP1a, on the functioning of the CB1R homodimer. The project is intended to verify a set of hypotheses: (i) homodimerization of the CB1R is agonist-mediated; (ii) the interface transmits cross-talk between protomers; (iii) cholesterol promotes CB1R homodimerization; (iv) cholesterol stabilizes the inactive state of the CB1R homodimer; (v) the CRIP1a stabilizes the inactive state of the CB1R monomer; (vi) the CRIP1a hampers CB1R homodimerization. The project involves the following detailed objectives: (1) homology modelling of the CB1R monomer in the active and inactive state; (2) application of protein-protein docking and surface roughness-based scoring to construct a model of the CB1R homodimer in the active, inactive and “mixed” state; (3) all-atom molecular dynamics (MD) simulations of respective dimers and monomers in a lipid bilayer; (4) all-atom MD simulations of the respective dimers and monomers in a lipid bilayer containing cholesterol; (5) modelling of CRIP1a; (6) modelling of the CB1R-CRIP1a complexes applying protein-protein docking and MD simulations; (7) coarse-grained MD to investigate the assembly of CB1R monomers and CB1R-CRIP1a complexes in a lipid bilayer; (8) coarse-grained MD to investigate the assembly of CB1R monomers and CB1R-CRIP1a complexes in a lipid bilayer containing cholesterol; (9) application of structure-based drug design methods to elaborate compounds that modulate dimer activity.'
Introduzione (Teaser)
Cannabinoid receptors are involved in many physiological processes responsible for memory, mood, pain and appetite. Modelling receptor interactions will empower their use as therapeutic targets.