Differential targeting of Gβγ-subunit signaling with small molecules

G protein beta gamma subunits have potential as a target for therapeutic treatment of a number of diseases. We performed virtual docking of a small-molecule library to a site on G beta gamma subunits that mediates protein interactions. We hypothesized that differential targeting of this surface could allow for selective modulation of G beta gamma subunit functions. Several compounds bound to G beta gamma subunits with affinities from 0.1 to 60 mu M and selectively modulated functional G beta gamma-protein-protein interactions in vitro, chemotactic peptide signaling pathways in HL-60 leukocytes, and opioid receptor-dependent analgesia in vivo. These data demonstrate an approach for modulation of G protein-coupled receptor signaling that may represent an important therapeutic strategy.