Fig. 3

Docking studies predicted molecular interactions characteristic of the 4,6-substituted 2-amino-pyridin-3-carbonitriles with the A_2AR protein crystal structure (PDB ID: 4EIY), A₁R homology model, and PDE10A protein crystal structure (PDB ID: 4DDL), which are displayed for representative multi-target ligands with the following combinations: compound 8 (A₁R–PDE10A), 18 (A₁R–A_2AR), and 25 (A_2AR–PDE10A): a interactions with A_2AR: the overlaid compounds 18 and 25 exhibit H-bonds via amino and carbonitrile groups with Asn₂₅₃, and the pyridine rings are π-stacked with Phe₁₆₈ b interactions with A₁R: the overlaid compounds 8 and 18 exhibit H-bonds via amino and carbonitrile groups with Asn₂₅₄, and the pyridine rings are π-stacked with Phe₁₇₁ c interactions with PDE10A: the overlaid compounds 8 and 25 have the pyridine rings π-stacked with Phe₆₈₆ and Phe₇₁₉. The molecular interactions predicted for the active molecules are consistent with observed interactions between co-crystallised ligands and their corresponding protein crystal structures (PDB ID: 4EIY and 4DDL) [33, 34] and the interactions with the A₁R homology model reported in the literature [51, 52]