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

Abstract

Phospholipase C-gamma (PLC-gamma) has been identi. ed 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-delta isoform was used as a model docking scaffold since no crystallographic data are available on its c counterpart. A pilot screen was performed using similar to 9.2 x 10(4) compounds, where the robustness of the methodology was tested. This was followed by the main screening effort where similar to 4.4 x 10(5) compounds were used. In both cases, plausible compounds were identi. ed ( 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 similar to 15 mu M in a functional assay in cells. About 30% of the virtual hits showed activity against PLC-gamma (IC50 < 50 mu M). (C) 2009 Elsevier Ltd. All rights reserved.