The characterization of the alcohol pocket in GIRK2 provided for a new strategy to virtually screen and design new drugs based on the binding properties of alcohol to its pocket. Employing this strategy, Zhao et al built a homology model of alcohol-bound GIRK2 to perform virtual screening for identifying new GIRK modulators that target the alcohol pocket [46]. The initial screening identified a small molecule, NCATS_2, which activated both GIRK2 and GIRK1/GIRK2 channels in heterologous expression systems. Subsequent analog screening revealed a variant of NCATS_2, named GiGA1, that preferentially activated GIRK1-containing GIRK channels (Figure 2B). Like ML297, GiGA1 activation is G-protein-independent, does not alter inward rectification of GIRK1/GIRK2, and exhibits preference for activating GIRK1/GIRK2 channels, as compared to GIRK1/GIRK4 or GIRK1/GIRK3 (Table 1) [46].
