Repurposing FDA-Approved Drugs Against Potential Drug Targets Involved in Brain Inflammation Contributing to...

Alzheimer's disease is a neurodegenerative disease that continues to have a rising number of cases. While extensive research has been conducted in the last few decades, only a few drugs have been approved by the FDA for treatment, and even fewer aim to be curative rather than manage symptoms. There remains an urgent need for understanding disease pathogenesis, as well as identifying new targets for further drug discovery. Alzheimer's disease (AD) is known to stem from a build-up of amyloid beta (Aβ) plaques as well as tangles of tau proteins. Furthermore, inflammation in the brain is known to arise from the degeneration of tissue and the build-up of insoluble material. Therefore, there is a potential link between the pathology of AD and inflammation in the brain, especially as the disease progresses to later stages where neuronal death and degeneration levels are higher. Proteins that are relevant to both brain inflammation and AD thus make ideal potential targets for therapeutics; however, the proteins need to be evaluated to determine which targets would be ideal for potential drug therapeutic treatments, or 'druggable'. Druggability analysis was conducted using two structure-based methods (i.e., Drug-Like Density analysis and SiteMap), as well as a sequence-based approach, SPIDER. The most druggable targets were then evaluated using single-nuclei sequencing data for their clinical relevance to inflammation in AD. For each of the top five targets, small molecule docking was used to evaluate which FDA approved drugs were able to bind with the chosen proteins. The top targets included DRD2 (inhibits adenylyl cyclase activity), C9 (binds with C5B8 to form the membrane attack complex), C4b (binds with C2a to form C3 convertase), C5AR1 (GPCR that binds C5a), and GABA-A-R (GPCR involved in inhibiting neurotransmission). Each target had multiple potential inhibitors from the FDA-approved drug list with decent binding infinities. Among these inhibitors, two drugs were found as top inhibitors for more than one protein target. They are C15H14N2O2 and v316 (Paracetamol), used to treat pain/inflammation originally for cataracts and relieve headaches/fever, respectively. These results provide the groundwork for further experimental investigation or clinical trials.