Acetylcholinesterase (AChE), with a rigid structure and buried active site at the end of a deep narrow gorge, is interesting enough to solve the paradox between high catalytic activity and unavailability of the active site in treatment of Alzheimer’s disease (AD). In this way, the blind docking process is performed on an ensemble of AChE structures created with molecular dynamics (MD) simulations to survey the whole space of AChE to find multiple access pathways to the active site and ranking them based on their affinity scores. Our results show that there are other allosteric binding sites in the protein structure whose inhibition, can affect protein function by disrupting the release of the Acetylcholine (AC) degradation products. In this study, inhibitory activities of Hybride14 and two natural compounds (Papaverine and Palmatine) were evaluated for all possible allosteric sites via docking method. The results confirmed the non-competitive inhibition mechanism. The best binding mode for these inhibitors and efficacy of hydrogen bonds and hydrophobic interactions on inhibitory activities of ligands were also disclosed. Furthermore, our studies provide significant molecular insight for AChE inhibition that could aid in the development of new drugs for AD’s treatment.
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