Discovery of small molecule inhibitors of MAO-B for Alzheimer’s disease using pharmacophore-based virtual screening
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Rory Hu
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Effective therapies are needed to mitigate Alzheimer’s disease (AD), a neurodegenerative dementia that harms cognitive function in over 10% of people older than 65. Although monoamine oxidase B (MAO-B) is a critical therapeutic target for AD, only three MAO-B inhibitors (rasagiline, selegiline, and safinamide) are currently approved, and they are mainly used for treating Parkinson’s Disease. To identify novel MAO-B inhibitors as treatments for AD, in silico drug discovery was employed as a cost-effective and efficient approach for screening a vast chemical space. Geometric, energetic, and machine learning methods were used to evaluate potential binding sites, which were subsequently assessed with molecular docking for 20 potential MAO-B inhibitors identified from pharmacophore mapping. These 20 molecules were then analyzed for their pharmacokinetic and toxicological properties via ADMET prediction, and Z56776036 and Z1980993192 were selected as the two most promising drug candidates. These lead compounds had high binding affinity (docking scores below -9 kcal/mol), strong ADME profiles, and low toxicity (LD50 values above 1000 mg/kg). This experiment proposes an innovative method of MAO-B inhibitor discovery. It represents a promising starting point for future work focused on further testing of the 2 lead compounds through in vitro screening and additional in silico discovery of lead compounds using the methodology of this project.
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Authors
Rory Hu
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References:
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