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Title: Dual Inhibitors of ROCK I and NOX to Attenuate Neuroinflammation in Neurological Disorders High Throughput Virtual and Biological screening
Keywords: ROCK-I and NOX2, Neurological Disorders, Biological screening
University: Birla Institute of Technology and Science
Completed Date: 
Abstract: Neurological diseases (ND) associated with inflammation are the most common form of dementia among both infantile and elderly. The disease is characterized by amyloid-and#946; (Aand#946;) plaques, synucleins, and neurofibrillary tangles, loss of synapses or neurons and chronic neuroinflammation. The significance of neuroinflammatory processes in attributed to both protective and damaging properties. However, patients systematically treated with anti-inflammatory drugs have been shown to develop ND to a lesser extent than average. This thesis focuses on four inflammatory related transcription factors, interleukin-6 (IL-6), interleukin-1and#946; (IL-1and#946;), tumor necrosis factor and#945; (TNF-and#945;) and nuclear factor and#954;B (NF-and#954;B) triggered by novel targets identified in neurological disorders. newlineTreating neuroinflammation in progressive neurological diseases is a remarkable strategy to obstruct superoxide generating inflammatory pathways. Two important targets identified to be crucial in progressive neuronal damage associated with neurodegeneration and neurodevelopmental disorders were ROCK-I and NOX2. NOX2 is a multi-enzyme component which is activated during host defence in phagocytes such as microglia, to catalyse the production of superoxide from oxygen. On the other hand ROCK-I is also an important mediator for fundamental cell processes like adhesion, proliferation and migration. Phosphorylated ROCK was found to activate NOX2 assembly via Ras related C3 botulinum toxin substrate (Rac) in inflammatory diseases. Thus, over expression of ROCK-I and NOX2 in microglial cells contributed to progressive neuronal damage early in neurodevelopmental and neurodegenrative disease development. newlineIn the present study, a diverse set of molecules as possible ROCK-I and NOX2 dual inhibitors were identified using structure based drug design strategy utilizing interaction energy and shape of the crystal ligands reported. Lead molecules thus obtained from the structure based design and virtual screening of databases were experimentally validated with in vitro enzymati
Pagination: 8.80 MB
Appears in Departments:Pharmacy

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