Inhibition of Acetylcholinesterase in Alzheimer’s Disease- an in Silico Approach

Alzheimer's disease (AD) is a progressive degenerative disease of the brain marked by gradual and irreversible declines in cognitive functions. Acetylcholinesterase plays a biological role in the termination of nerve impulse transmissions at cholinergic synapses by rapid hydrolysis of acetylcholine. The deficit levels of acetylcholine lead to poor nerve impulse transmission. Thus the cholinesterase inhibitors would reverse the deficit in acetylcholine levels and consequently reverse the memory impairments characteristic of the disease. In the present work, functionalized coumarin compounds and their derivatives were docked into active site of Acetylcholinesterase using the docking programs GOLD and GLIDE. The compounds were screened using High throughput screening, and further subjected to Induced Fit Docking studies. Further, the QSAR studies revealed the best structure activity relationship and 100% of human oral absorption. The inhibitor compounds also satisfied the PASS (Prediction of Activity Spectra for Substances) results of inhibiting the activity of acetylcholinesterase. The type of interaction they exhibit and the residues with which they interact convey that both the compounds are good inhibitors of Acetylcholinesterase as they exhibit drug like activity. INTRODUCTION: Alzheimer's disease (AD), also called Alzheimer disease, Senile Dementia of the Alzheimer Type (SDAT) or simply Alzheimer’s is the most common form of dementia. Alzheimer's disease (AD) is a slowly progressive disease of the brain that is characterized by impairment of memory and eventually by disturbances in reasoning, planning, language, and perception 1 (Fig. 1). AD neuropathological hallmarks include extracellular deposits of amyloid-β (Aβ) peptides (amyloid hypothesis), intracellular neurofibrillary tangles (tau hypothesis), neuronal and synaptic degeneration/loss, and neuroinflammation. FIG. 1: COMPARISON OF A NORMAL AGED BRAIN (LEFT) AND AN ALZHEIMER'S PATIENT'S BRAIN (RIGHT)