Table 1.
Assay Protocol.
Figure 1.
Compound Identification Flow Chart.
Depicted is a flow chart of the assays, filtering, and analyses that were performed to ultimately identify the 7 chemotypes of clusters of molecules that have been selected for further study.
Table 2.
Summary of Confirmation Hits.
Figure 2.
A 3-axis plot of the 1356 compounds identified in the confirmation assay is shown. Compounds are sorted by curve class. Red: active compounds in curve class 1 and 2. Green: weakly active compounds in curve class 3. Blue: inactive compounds in curve class 4.
Figure 3.
Active compounds were clustered based on structural similarity to identify common chemotypes using LeadScope (Leadscope Hosted Client, Leadscope Inc., Columbus, OH). The results show a diversity of structural clusters, with 22 distinct clusters with more than 5 members. (A) Representative compounds from each of the most prominent 7 clusters are shown. (see Table S5, Cluster Analysis Compounds with Link for a complete list of the 102 molecules in the 7 clusters, their structures, IC50, and active link to the complete PubChem description). Their common structural scaffolds are highlighted in red. These scaffolds are highly polar, including thiazole, triazole, and hydrozide-based derivatives. Another common structural feature is that these small molecules share a linear molecular shape, which suggests that they might compete with GTP at the active site of the G protein. (B) Inhibition-concentration curves for 7 selected compounds, one from each cluster, together with the IC50 for each compound are shown.