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Identification of Small-Molecule Frequent Hitters of Glutathione S-Transferase-Glutathione Interaction

: Brenke, J.K.; Salmina, E.S.; Ringelstetter, L.; Dornauer, S.; Kuzikov, M.; Rothenaigner, I.; Schorpp, K.; Giehler, F.; Gopalakrishnan, J.; Kieser, A.; Gul, S.; Tetko, I.V.; Hadian, K.


Journal of biomolecular screening 21 (2016), No.6, pp.596-607
ISSN: 1087-0571
Journal Article
Fraunhofer IME ()

In high-throughput screening (HTS) campaigns, the binding of glutathione S-transferase (GST) to glutathione (GSH) is used for detection of GST-tagged proteins in protein-protein interactions or enzyme assays. However, many false-positives, so-called frequent hitters (FH), arise that either prevent GST/GSH interaction or interfere with assay signal generation or detection. To identify GST-FH compounds, we analyzed the data of five independent AlphaScreen-based screening campaigns to classify compounds that inhibit the GST/GSH interaction. We identified 53 compounds affecting GST/GSH binding but not influencing His-tag/Ni2+-NTA interaction and general AlphaScreen signals. The structures of these 53 experimentally identified GST-FHs were analyzed in chemoinformatic studies to categorize substructural features that promote interference with GST/GSH binding.