Screening and analysis of acetyl-cholinesterase (AChE) inhibitors in the context of Alzheimer’s disease

Abstract

Acetyl-cholinesterase enzyme (AChE) is a known target for identifying potential inhibitors against Alzheimer diseases (AD). Therefore, it is of interest to screen AChE with the CNS-BBB database. An AChE enzyme is a member of hydrolase family is activated by acetylcholine (ACh), so, targeting the AChE enzyme with the potential inhibitor may block the binding of the ACh. In this study we carried out virtual screening of drug-like molecules from Chemical Diversity Database particularly CNS-BBB compounds, to identify potential inhibitors using Glide docking program. Top ranking ten compounds, which have lower Glide Score when compared to known drugs (Tacrine and Galantamine) for AChE. For top three molecules MD simulation was carried out and calculated binding free energy. We report the best binding compounds with AChE compared to known drugs (Taine and Galantamine) for AD. We further document the salient features of their molecular interaction with the known target. Three molecules (1-benzyl-3-(2- hydroxyethyl)-N-[2-(3-pyridyl)ethyl]-3-pyrrolidinecarboxamide, N-{3[benzyl(methyl)amino]propyl}-1,5-dimethyl-4-oxo-4,5-dihydro- 1H-pyrrolo[3,2-c]quinoline-2-carboxamide, and 6-chloro-N-[2-(diethylamino)-2-phenylethyl]-4-oxo-4H-chromene-2-carboxamide) have -196.36, -204.27, -214.40 kJ/mol, binding free energy values respectively which are much lower than values calculated for the reference ligands Tacrine and Galantamine having -119.65 and -142.18 kJ/mol respectively. Thus these molecules can be very novel potential inhibitors against AChE involved in Alzheimer's disease.

Structural Fractal Analysis of the Active Site of Acetylcholinesterase in Complexes with Huperzine A, Galantamine, and Donepezil

“…These changes are most frequently observed in Glu202 (F = 8/12 = 0.67). It is important to note that this effect is observed in all hAChE crystalline complexes with huperzine A, galantamine, and donepezil, which is consistent with the data in [51][52][53][54] indicating the participation of Glu202 in the formation of hAChE/AChE complexes with various ligands. The AARs Tyr72, Asp74, Leu76, Tyr124, Tyr133, and His447 are involved in the complex formation to a much lesser extent (F = 2/12 = 0.17).…”

“…The structural changes related to these AARs were also noted. [51,[54][55][56] Single insignificant structural perturbations (F = 1/12 = 0.08) are also observed in the case of Thr75, Gly121, Ser203, Trp236, Trp286, Phe295, Phe297, Glu334, and Tyr337. Finally, the complete absence of structural changes was detected for Trp86, Gly122, Ala204, Phe338, Tyr341, Gly448, and Ile451.…”

Composition of the essential oil of Satureja metastasiantha : a new species for the flora of Turkey

“…BChE is found in glial cells, neurons, and neuritic plaques [27]. Galanthamine is used frequently to treat the symptoms of Alzheimer's disease as an AChE inhibitor [28], which hydrolyses the acetylcholine compound involved in the communication between synapses in the nervous system. Thus, it is very important to cure Alzheimer's disease.…”

Quercetin-Conjugated Superparamagnetic Iron Oxide Nanoparticles Protect AlCl3-Induced Neurotoxicity in a Rat Model of Alzheimer’s Disease via Antioxidant Genes, APP Gene, and miRNA-101

“…AChE plays an important role in synapses and connections between neurons and muscles ( Mathew et al, 2019 ). As AD progresses, impairments in neuron transmission also increase ( Khan et al, 2018 ). In accordance, elevated activity of AChE is observed in the brain tissue of AD patients, and the meaningful increase in the hippocampus of rat models treated with AlCl 3 is reported ( Pourshojaei et al, 2019 ; Zambrano et al, 2019 ).…”