Molecular modeling of a PAMAM-CGS21680 dendrimer bound to an A2A adenosine receptor homodimer

The theoretical possibility of bivalent binding of a dendrimer, covalently appended with multiple copies of a small ligand, to a homodimer of a G protein-coupled receptor was investigated with a molecular modeling approach. A molecular model was constructed of a third generation (G3) poly(amidoamine) (PAMAM) dendrimer condensed with multiple copies of the potent A2A adenosine receptor agonist CGS21680. The dendrimer was bound to an A2A adenosine receptor homodimer. Two units of the nucleoside CGS21680 could occupy the A2A receptor homodimer simultaneously. The binding mode of CGS21680 moieties linked to the PAMAM dendrimer and docked to the A2A receptor was found to be similar to the binding mode of a monomeric CGS21680 ligand.