Zanapezil, a Potential Repurposable Drug Against Huntington Disease: An In Silico Forecast

Huntington’s Disease (HD), a fatal neurodegenerative disorder, is an autosomal dominant condition characterized by improper involuntary movements of the voluntary muscles (chorea), dystonia, difficulty in speech and cognitive impairment along with psychiatric symptoms. On an average the disease affects about 0.25% (∼7000 individuals) of the general population. Pathophysiology of HD involves mutation in Huntingtin (HTT) gene due to repetition of CAG nucleotide, characterized by degeneration or loss of medium spiny neurons resulting in atrophy of striatal region. The early development of the disease also shows a significant slimming of cortical ribbon and proceeds from posterior to anterior portion of the cortical regions. Further, neurodegeneration is attributed to mitochondrial dysregulation leading to decrease in ATP production and loss in calcium buffering capacitance eventually leading to apoptosis. Tetrabenazine, a current FDA approved drug for the treatment of HD, used to treat choreiform movements, inhibits Vesicular Monoamine Transporter (VMAT2) protein which is involved in the storage and release of dopamine. The appropriate treatment for the disease is still under research.