Several studies have suggested that disrupting interactions of the G protein betagamma subunits with downstream binding partners might be a valuable study for pharmaceutical development. Recently, small molecules have been found which bind to Gbetagamma with high apparent affinity in an enzyme-linked immunosorbent assay (ELISA), have demonstrated selective inhibition of interactions of Gbetagamma with downstream signaling partners, and have been shown to increase antinociceptive effects of morphine and inhibit inflammation in vivo. In this paper we examine several docking and scoring protocols for estimating binding affinities for a set of 830 ligands from the NCI diversity set to the Gbeta1gamma2 subunit and compared these with IC50s measured in a competition ELISA with a high-affinity peptidic ligand. The best-performing docking protocol used a consensus score and ensemble docking and resulted in a 6-fold enrichment of high-affinity compounds in the top-ranked 5% of the ligand data set.