Virtual Screening against Phosphoglycerate Kinase 1 in Quest of Novel Apoptosis Inhibitors.

Inhibition of apoptosis is a potential therapy to treat human diseases such as neurodegenerative disorders (e.g., Parkinson's disease), stroke, and sepsis. Due to the lack of druggable targets, it remains a major challenge to discover apoptosis inhibitors. The recent repositioning of a marketed drug (i.e., terazosin) as an anti-apoptotic agent uncovered a novel target (i.e., human phosphoglycerate kinase 1 (hPgk1)). In this study, we developed a virtual screening (VS) pipeline based on the X-ray structure of Pgk1/terazosin complex and applied it to a screening campaign for potential anti-apoptotic agents. The hierarchical filters in the pipeline (i.e., similarity search, a pharmacophore model, a shape-based model, and molecular docking) rendered 13 potential hits from Specs chemical library. By using PC12 cells (exposed to rotenone) as a cell model for bioassay, we first identified that AK-918/42829299, AN-465/41520984, and AT-051/43421517 were able to protect PC12 cells from rotenone-induced cell death. Molecular docking suggested these hit compounds were likely to bind to hPgk1 in a similar mode to terazosin. In summary, we not only present a versatile VS pipeline for potential apoptosis inhibitors discovery, but also provide three novel-scaffold hit compounds that are worthy of further development and biological study.