Identification of Nrf2 Activators Using an In Silico Modeling Platform, Followed by Evaluation of These Compounds in an Alpha-Synuclein Model of PD
MJFF Research Grant, 2011
Oxidative stress has been implicated in the etiology of Parkinsonís 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 Nrf2ĖARE pathway in the brain confers protection to vulnerable neurons, making neuronal Nrf2 up-regulation an attractive therapeutic strategy for PD.
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 compoundsí in vivo distribution and activity and to experimentally evaluate if these novel Nrf2 activators will confer neuroprotection in a pre-clinical MPTP Parkinsonís 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 Parkinsonís Disease:††
A focused effort to find novel compounds that cross the bloodĖbrain 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.
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.
INTERIM PROGRESS REPORT
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 and possess higher activity than prototypical Nrf2 modulators tBHQ and sulforaphane in primary cortical neurons. †Preliminary experiments displayed blood brain barrier penetration and Nrf2 activation in vivo for the lead compound GB822. The compounds also showed protection of dopaminergic neurons in vitro; however their inconsistent solubility and gut permeability produced inconclusive in vivo neuroprotection results in an MPTP pre-clinical model. In the future, we will explore ways to improve solubility of GB822, or to bypass the gut via alternative delivery of the compound. Additionally, the versatility of Gradientís quantum-based drug discovery approach enabled the de novo design of new chemical entities with the same Nrf2 activation properties as GB822, but with optimized solubility and other pharmacological characteristics.
Presentations & Publications
Discovery of potent, novel Nrf2 inducers via quantum modeling, virtual screening and in†vitro experimental validation. Tracy P. Williamson, Sara Amirahmadi, Gururaj Joshi, Nikola K. Kaludov, Martin N. Martinov, Delinda A. Johnson, Jeffrey A. Johnson
Chemical Biology & Drug Design, Volume 80, Issue 6, pages 810Ė820, December 2012
Identification of Nrf2 Activators Using an In Silico Modeling Platform, Followed by Evaluation of These Compounds in an Alpha-Synuclein Model of Parkinsonís Disease. Martin N. Martinov, Gradient Biomodeling LLC
6th Annual Parkinsonís Disease Therapeutics Conference, October 24th, 21012 New York City
Chief Scientific Officer at Gradient Biomodeling LLC
Location: Park City, Utah, United States
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