Figure 6. Flexible receptor consensus binding modes for adenosine receptor PAMs showing the receptor surface and orientations of 3-point pharmacophores.

Following extensive sampling of the entire extracellular receptor surface for each compound, top-ranked clusters from flexible docking were identified supporting a consensus binding mode over several chemical series. The binding modes of azaadenines 7 and 8 are very similar to that of 9 (LUF6000) and 10 (LUF6096). The A_2AR and A₃R selective PAMs 8–10 are compared to the A₁R PAMs 3 and 4 and similar pharmacophore features from the common binding modes are mapped onto 2D structures. For example, the aryl amines of 7–10 form similar binding interactions with the ECL2 loop, similar to the 1-amino group of the thiophene in 3 and 4. For simplicity, the compounds are all shown on the receptor surface. Supplementary Figure 3. shows the exact same poses with corresponding protein-ligand interactions with specific amino acids.