This project aims to develop potent small molecule activators of Parkin, which is mutated in some forms of familial Parkinson’s disease and might also be inactivated in sporadic disease. Together with PINK1, Parkin is responsible for the destruction of harmful damaged mitochondria. Our ultimate goal is to develop activators of Parkin’s enzymatic functions and to test these molecules in models of PD for neuroprotective effects.
Under normal conditions the Parkin enzyme is very compact and it needs to open up in order to become active. We have generated an all-atom resolution model of human Parkin protein from incomplete crystal structure(s) by molecular modeling and used dynamics simulation to generate a sequence of events that unfold Parkin’s compact structure in silico. With this we can predict molecules that bind to particular regions, lead to structural changes and open up Parkin’s configuration or keep it in an open, i.e. active, position. Candidate molecules are tested in cells that have been engineered to report the activation of Parkin by high-content imaging with an automated microscope. We have already generated first actives that will be developed further by re-iterating our predictions in a ‘hit explosion.’ These new candidates will be tested in cells and the results used to further our computer predictions. Our goal is to develop non-toxic highly potent small molecules with optimized biological characteristics (absorption, distribution, metabolism and excretion).
Relevance to Diagnosis/Treatment of Parkinson’s Disease:
Parkin has been shown to be neuroprotective in different paradigms. Therefore, strategies aiming at safely activating and maintaining Parkin in a catalytically active state could prove beneficial and might open up new avenues to treat Parkinson’s disease in the future.
Using our accelerated drug discovery platform that combines cutting-edge technologies for computer-based and cell-based screening, we expect to further improve our set of small molecule Parkin activators. In subsequent follow-up studies, these will be tested in different models as neuroprotective agents.