E-Pharmacophore Model Assisted Discovery of Novel Antagonists of nNOS

Alzheimer’s disease (AD) is the most common form of dementia characterized clinically with progressive cognitive decline and neuronal loss. Pathologically, AD affected brain shows accumulation of β-amyloid (Aβ) plaques and neurofibrillary tangles formed by the hyper phosphorylation of tau protein. Recent studies indicate that mitochondrial dysfunction, a pathological featurethat can be detected early in AD. Nitric oxide synthases (NOS) are a family of enzymes catalyzing the production of nitric oxide (NO), which functions as neuronal signalingmolecule. Altered expression of nNOS by the Aβ stimulus results in the formation of peroxy nitrite and reactive oxygen species. These peroxy-nitrite, nitrosylates the cytoplasmic protein tau and phosphorylates GSK-3β.

Nitrosylation of tau protein results in structural and conformational change of tau protein ensuring the destabilization of microtubule. This leads to dissociation of tau protein from microtubule and oligomerization of tau occurs to form neuro-fibrillary tangles (NFT’s). These tangles forms a physical road blocks within the neuronal cells and interrupts the neurotransmitter signaling.