Identification of Nrf2 Activators Using an In Silico Modeling Platform, Followed by Evaluation of These Compounds in an Alpha-Synuclein Model of PD

Objective/Rationale: 
Oxidative stress has been implicated in the etiology of Parkinson’s disease (PD). Under such conditions, the transcription factor NF-E2-related factor (Nrf2) binds to antioxidant response element (ARE) to induce antioxidant and phase II detoxification enzymes. Numerous studies suggest that activation of the Nrf2–ARE pathway in the brain confers protection to vulnerable neurons, making neuronal Nrf2 up-regulation an attractive therapeutic strategy for PD.

Project Description: 
Using a unique, quantum-based computational process for drug discovery and design, Gradient Biomodeling, LLC has identified two potent, chemically novel Nrf2 pathway activators. The compounds are non-toxic, their activity is higher than prototypical Nrf2 modulators tBHQ and sulforaphane in primary cortical neurons and preliminary experiments show blood brain barrier penetration and Nrf2 activation in vivo for the lead compound. The main objective of this project is to confirm the compounds’ in vivo distribution and activity and to experimentally evaluate if these novel Nrf2 activators will confer neuroprotection in a pre-clinical MPTP Parkinson’s disease model. This research will enable the de novo design of new chemical entities with therapeutic PD properties through Nrf2 and optimized pharmacological characteristics.

Relevance to Diagnosis/Treatment of Parkinson’s Disease:  
A focused effort to find novel compounds that cross the blood–brain barrier efficiently, activate the Nrf2-ARE pathway in the brain, and have efficacy against oxidative stress-induced neurotoxicity could be pivotal in halting the progression of PD through the development of new therapeutic approaches targeting this pathway.

Anticipated Outcome: 
Upon the successful completion of this project, Gradient will have evaluated the PD therapeutic potential of a lead molecule, capable of activating the Nrf2-ARE pathway in vivo. Moreover, we will have experimentally validated our Nrf2/PD quantum model, which will provide not only powerful means to assess the risk of taking compounds further in the pharmaceutical development process but will also generate important information that will allow for de novo design of additional, novel, fully optimized compounds with PD therapeutic potential.