In Silico Discovery of Natural NNMT Inhibitors as Alzheimer’s Disease Therapeutics

Alzheimer’s disease (AD) is the most common dementia type, affecting around 8.8% of Singaporeans aged 60 and above. No effective therapies exist, and drug development has yet to achieve consistent clinical improvement.

Recent findings highlight the role of nicotinamide adenine dinucleotide (NAD+) metabolism in AD and brain health. NAD+ is essential for energy metabolism and DNA repair; its depletion is implicated in AD pathology. Another critical alteration observed in AD is epigenetic changes of the brain. These have been linked to risk and progression of AD, likely contributing to the dysregulation of AD-related gene expression.

In mammals, the primary methyl donor involved in DNA methylation events is S-adenosylmethionine (SAM), whose modulation has also been linked to AD.

Importantly, the cross-talk between NAD+ metabolism and SAM-mediated methylation processes is controlled by the enzyme nicotinamide N-methyltransferase (NNMT). NNMT uses SAM to methylate nicotinamide (NAM), a vital NAD+ precursor, impacting NAD+ synthesis. Increased NNMT expression in AD disrupts both NAD+ and epigenetic regulation, making NNMT inhibition a promising therapeutic approach to optimize NAD+ and SAM in the brain, potentially slowing AD progression.

This project aims to discover and validate the first natural NNMT inhibitors to ameliorate AD pathology. The approach includes in silico compound library screenings and NNMT structure prediction, validation of inhibitors in neuronal cells, and mechanistic exploration in AD rodent models. Identifying first-in-class natural NNMT inhibitors for brain health applications holds potential for rapid clinical development of supplements or novel pharmaceuticals, offering an alternative approach to managing AD and related conditions.