REPURPOSING OF DRUGS FOR GLUTAMATE RECEPTOR IN HUNTINGTON’S DISEASE: A BIOINFORMATICS EXPEDITION

Abstract

Aim: A rare hereditary illness called Huntington's disease (HD) is typified by the build-up of mutant huntingtin protein aggregates. The aggregates cause excitotoxicity, which in turn causes neuronal malfunction and ultimately results in cell death. Glutamate receptors, in particular the NMDA receptors (NMDARs), which are made up of NR1 and NR2 subunits and form a heteromeric complex required for receptor activation, are partially responsible for excitotoxicity in HD. In HD, overactivation of NMDARs causes brain symptoms and neuronal damage. A possible therapeutic strategy involves blocking the NMDAR NR1 and NR2 subunits. Through the use of databases and bioinformatic computational tools, researchers hope to decrease development periods and minimize safety and toxicity issues by repurposing existing drugs to block NMDARs. Identified the 19 antipsychotic medications with the greatest outcomes against the NMDA receptor by using bioinformatic computational tools and approaches. PyRx-Vina was utilized for molecular docking, while Discovery Studio was employed to visualize the interactions between ligands and proteins. When compared to ketamine, an FDA-approved medication utilized as a reference antagonist, we discovered that aripiprazole produced favourable results. By inhibiting NMDAR activity and lowering dopamine production, inhibition of NR1 and NR2 subunits lessens excitotoxic neuronal damage in HD. Repurposing already-approved medications has advantages like accelerated time to market, decreased toxicity, and fewer safety risks. Result: Identified the 19 antipsychotic medications with the greatest outcomes against the NMDA receptor by using bioinformatic computational tools and approaches. PyRx-Vina was utilized for molecular docking, while Discovery Studio was employed to visualize the interactions between ligands and proteins. When compared to ketamine, an FDA-approved medication utilized as a reference antagonist, we discovered that aripiprazole produced favourable results. By inhibiting NMDAR activity and lowering dopamine production, inhibition of NR1 and NR2 subunits lessens excitotoxic neuronal damage in HD. Repurposing already-approved medications has advantages like accelerated time to market, decreased toxicity, and fewer safety risks. This research indicates that Huntington's illness may be treated therapeutically with aripiprazole due to its inhibition of NMDAR. Molecular docking experiments indicate that apipirazole has a high binding affinity and forms Stable interaction with key sites in the NMDAR. It has favourable pharmacokinetic properties, such as high solubility, low toxicity, and blood-brain barrier bridging, and a higher binding affinity than ketamine. Conclusion: Repurposed drug of drug candidates originally known for as Bipolar disorder, Anti-Depression categories for treating for Huntington Disease who have glutamatergic effect by targeting its NMDA Receptor, an glutamate receptor by targeting this receptor can inhibit the excess excitotoxicity in Huntington’s disease. Apipirazole has a high binding affinity and forms Stable interaction with key sites in the NMDAR. It has favourable pharmacokinetic properties, such as high solubility, low toxicity, and blood-brain barrier bridging, and a higher binding affinity than ketamine.