Identification of Putative LRRK2 Inhibitors in the Pathogensis of Parkinson's Disease: A Drug-Repurposing Approach

One of the most common causes of Parkinson's disease are mutations in the enzyme LRRK2 or leucine-rich-repeat kinase 2. Out of all known mutations in this enzyme, the G2019S mutation is the one most commonly studied. This mutation greatly increases the kinase activity and phosphorylates many molecules of an apoptotic nature. We curated a list of 225 FDA approved drugs for the purpose of re-positioning them as an inhibitor for the aberrant LRRK2. Literature presents a substantial correlation between the pathologies of cancer, diabetes, cardiovascular disorders and Parkinson's. Thus, drugs targeting these diseases can be effectively re-purposed for PD on account of shared pathologies. Through molecular docking analysis we identified venetoclax, an anti-cancer drug, as a potent inhibitor of both wild-type LRRK2 and the G2019S mutant. Further analysis showed that venetoclax also inhibits Hsp90, which has a marked anti-apoptotic effect because it targets the enzyme LRRK2 for proteasomal degradation.