Abstract
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. Probucol treatment regulates lipid droplet dynamics during mitophagy and ABCA1 is required for these effects. Here we will summarize the combination of in silico and cell-based screening that led us to identify and characterize probucol as a compound that enhances mitophagy and include thoughts about future directions for the topics explored in our study.Abbreviations: ABCA1: ATP binding cassette transporter protein 1; ATP: Adenosine tri-phosphate; CCCP: carbonyl cyanide m-chlorophenylhydrazone; DsRed: Discosoma red; FDA: Food and drug administration; GFP: Green fluorescent protein; LAMP: lysosome-associated membrane glycoproteins; LD: Lipid droplet; PD: Parkinson's disease; PINK: PTEN-induced kinase.