From jeopardy champion to drug discovery; semantic similarity artificial intelligence.

We have employed artificial intelligence to streamline the small molecule drug screening pipeline and identified the cholesterol-reducing compound probucol in the process. Probucol augmented mitophagy and prevented loss of dopaminergic neurons in flies and zebrafish challenged with mitochondrial toxins. Further dissection of the mechanism of action led to the identification of ABCA1, the target of probucol, as a mitophagy modulator.

An AI-guided screen identifies probucol as an enhancer of mitophagy through modulation of lipid droplets.

Failures in mitophagy, a process by which damaged mitochondria are cleared, results in neurodegeneration, while enhancing mitophagy promotes the survival of dopaminergic neurons. Using an artificial intelligence platform, we employed a natural language processing approach to evaluate the semantic similarity of candidate molecules to a set of well-established mitophagy enhancers. Top candidates were screened in a cell-based mitochondrial clearance assay.

ROCK inhibitors upregulate the neuroprotective Parkin-mediated mitophagy pathway.

The accumulation of damaged mitochondria causes the death of dopaminergic neurons. The Parkin-mediated mitophagy pathway functions to remove these mitochondria from cells. Targeting this pathway represents a therapeutic strategy for several neurodegenerative diseases, most notably Parkinson's disease.

A Rhomboid in the Rough: Potent Inhibitors for a Previously Undruggable Target.

In this issue of Cell Chemical Biology, Tichá et al. (2017) report a novel class of highly potent and selective rhomboid inhibitors. Rhomboids are implicated in several devastating human afflictions including malaria, diabetes, cancer, and Parkinson's disease (PD), making them important drug targets for future therapeutics.