IDENTIFICATION OF PUTATIVE INHIBITORS OF MUTANT LRRK2 INVOLVED IN1THE1PATHOGENESIS1OF1PARKINSON’S DISEASE: AN IN-SILICO DRUG RE-PURPOSING APPROACH

Abstract

One of the most common causes of Parkinson’s disease are mutations in the enzyme LRRK2 or leucine-rich-repeat kinase 2 or LRRK2. Out of all known mutations in this enzyme, the G2019S mutation is the one commonly studied. This mutation greatly increases the kinase activity and phosphorylates many molecules of an apoptotic nature. In this study we curated a list of various FDA-approved anti-cancer, anti-diabetic and anti hypertensive drugs to re-purpose them against Parkinson’s. Literature shows a correlation in the pathologies of cancer, diabetes, cardiovascular disorders and PD. Thus, these drugs can therefore be repurposed on account of the disease’s shared pathology. By using a molecular docking approach, we identified Venetoclax, a Bcl-2 inhibitor prescribed for the treatment of cancer, as a very potent inhibitor of the G2019S mutant of LRRK2. On further analysis, it showed that Venetoclax, in addition to the G2019S mutant also inhibits Hsp90 (a part of the CHIP ubiquitin E3-ligase system) thereby possessing dual functionality. This inhibition of two targets has marked anti-apoptotic effects as it not only helps control the aberrant kinase activity of the G2019S mutant, it also increases the clearance of the mutant LRRK2 through the ubiquitin-proteasome pathway.