ZANAPEZIL,A POTENTIAL REPURPOSABLE DRUG AGAINST HUNTINGTON DISEASE:AN IN SILICO FORECAST

摘要

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 [1].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 [2] [3].The appropriate treatment for the disease is still under research.Contemporary research is focussed on drug repurposing which explores new therapeutic indications for existing drugs rather than de novo drug discovery to circumvent the hiccups involved in the later process.Many repurposing trials have come up based on existing omics data to identify the novel repurposable targets.In fact,handful of repurposing projects reached the heights of clinical trials.Some of the repurposed drugs in clinical trials for HD are Pridopidine under phase 2 trials(NCT01306929)[4];Cysteamine under phase 2/3(NCT02101957)and Latrepiridine under phase 3 trials(NCT00920946)[2],[5].The present research is an in silico approach to predict disease specific targets and drugs.In this work,we extracted Differentially Expressed Genes(DEGs)in HD through Gene Expression Omnibus(GEO)dataset,studied their interaction with literature derived reported genes through Protein-Protein Interaction(PPI)network analysis using Search Tool for Retrieval of Interacting Genes(STRING).Finally,the shortlisted targets were subjected to molecular docking with FDA approved drugs from Drugbank database to identify the potential anti-HD drugs.