Abstract
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.
Highlights
Apoptosis is the death of a cell regulated by a tight intracellular program [1]
In order to validate the efficacy of the pipeline, we further apply it to screening the Specs chemical library and test potential hits for their preliminary protective effects on PC12 cells exposed to rotenone
By comparing the cell viability of PC12 cells treated with rotenone, with rotenone plus compounds, we found that AN-465/41520984, AK-918/42829299, and AT-051/43421517 potentially protected PC12 cells against rotenone-induced cell death by increasing cell viability
Summary
Apoptosis is the death of a cell regulated by a tight intracellular program (i.e., programmed cell death) [1]. The precise control of apoptosis is indispensable to maintain the homeostasis of development and the aging of tissues and normal immune defense, while the abnormal regulation of apoptosis could cause many human conditions [2]. Activated apoptosis has been identified in the development of neurodegenerative disorders (e.g., Parkinson’s disease) [3], stroke [4], and sepsis [5]. The main targets for the discovery of small-molecule apoptosis inhibitors have been cysteine aspartate-specific proteases (caspases) that directly mediate apoptosis [6,7]. Though great efforts were taken, no caspase inhibitor has been approved for clinical use so far [12]
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