The identification of novel PLC-γ inhibitors using virtual high throughput screening

Phospholipase C-γ (PLC-γ) has been identified as a possible biological target for anticancer drug therapy but suitable inhibitors are lacking. Therefore, in order to identify active compounds (hits) virtual high throughput screening was performed. The crystal structure of the PLC-δ isoform was used as a model docking scaffold since no crystallographic data are available on its γ counterpart. A pilot screen was performed using ∼9.2 × 104 compounds, where the robustness of the methodology was tested. This was followed by the main screening effort where ∼4.4 × 105 compounds were used. In both cases, plausible compounds were identified (virtual hits) and a selection of these was experimentally tested. The most potent compounds were in the single digit micro-molar range as determined from the biochemical (Flashplate) assay. This translated into ∼15 μM in a functional assay in cells. About 30% of the virtual hits showed activity against PLC-γ (IC50 < 50 μM).

Phospholipase C-γ (PLC-γ) is as a potential biological target for anticancer drug therapy. Virtual high throughput screening was performed using ∼5.3 × 105 compounds to identify hits. The most potent compounds according to a biochemical assay were in the low single digit micro-molar range which translated into a GC50 of ∼15 μM for a functional assay in cells. About 30% of the compounds tested were active (IC50 < 50 μM) and were structurally diverse.Figure optionsDownload as PowerPoint slide