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Galantamine is one of the approved drugs based on the cholinergic hypothesis for the symptomatic treatment of mild to moderate Alzheimer’s disease (AD). The etiology of AD is not fully known; however, the reported cholinergic hypothesis suggests the inadequate synthesis of the neurotransmitter acetylcholine (ACh) is responsible for this disease. The crystal structure of galantamine bound human acetylcholinesterase ( h AChE) has been reported; however, the inhibition mechanism of  h AChE by galantamine is not well understood. A Well-tempered metadynamics (WTMtD) simulation study has been performed with the crystal structure of galantamine bound  h AChE. The reported mechanism for the degradation of ACh is suggested through a proton transfer process from a carboxylic group of Glu334 to the hydroxyl group of Ser203, which attacks ACh for the degradation to acetic acid and choline. Such proton transfer process is lowered in the presence of galantamine due to the separation of catalytic triad inside the gorge of AChE as observed with WTMtD. A docking study has been performed to examine the ACh's binding with the catalytic triad of galantamine bound  h AChE. The docking results reveal that the approach of ACh to the catalytic triad is interrupted due to the galantamine's presence in the gorge of the enzyme.

Revealing the cholinergic inhibition mechanism of Alzheimer’s by galantamine: a metadynamics simulation study