An <i>in silico</i> approach to identify potential medicinal plants for treating Alzheimer disease: a case study with acetylcholinesterase

Potshangbam, Angamba Meetei; Apana, Nandeibam; Amom, Thongamba; Nongdam, Potshangbam; Rahaman, Hamidur; Rathore, R. S.; Singh, Laishram Rajendrakumar; Khan, Aslam

doi:10.1080/07391102.2020.1828170

Cited by 11 publications

(8 citation statements)

References 54 publications

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“…For all complexes with AChE and BuChE, the BFE decomposition indicated that van der Waals energy was the main force guiding the enzyme−ligand binding, similar to previous studies with AChE. 56 Considering AChE complexes, Phe388 was the residue that most contributed to AChE-4a formation while for the other complexes it was Trp286 (Supporting Information: -Figure S7). Residues Phe297, Phe338, and Tyr341 contributed to all the complexes formation, reinforcing the importance of aromatic moieties in the ligand for interaction with residues from the acyl pocket, PAS, and CAS, respectively.…”

Section: In Silico Evaluation Of N-benzylpiperidine Derivatives With ...supporting

confidence: 79%

Structure‐based design of new N‐benzyl‐piperidine derivatives as multitarget‐directed AChE/BuChE inhibitors for Alzheimer's disease

Conceição,

von Ranke,

Azevedo

et al. 2023

J of Cellular Biochemistry

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The pathogenic complexity of Alzheimer's disease (AD) demands the development of multitarget‐directed agents aiming at improving actual pharmacotherapy. Based on the cholinergic hypothesis and considering the well‐established role of butyrylcholinesterase (BuChE) in advanced stages of AD, the chemical structure of the acetylcholinesterase (AChE) inhibitor drug donepezil (1) was rationally modified for the design of new N‐benzyl‐piperidine derivatives (4a−d) as potential multitarget‐direct AChE and BuChE inhibitors. The designed analogues were further studied through the integration of in silico and in vitro methods. ADMET predictions showed that 4a−d are anticipated to be orally bioavailable, able to cross the blood‐brain barrier and be retained in the brain, and to have low toxicity. Computational docking and molecular dynamics indicated the formation of favorable complexes between 4a−d and both cholinesterases. Derivative 4a presented the lowest binding free energy estimation due to interaction with key residues from both target enzymes (−36.69 ± 4.47 and −32.23 ± 3.99 kcal/mol with AChE and BuChE, respectively). The in vitro enzymatic assay demonstrated that 4a was the most potent inhibitor of AChE (IC50 2.08 ± 0.16 µM) and BuChE (IC50 7.41 ± 0.44 µM), corroborating the in silico results and highlighting 4a as a novel multitarget‐directed AChE/BuChE inhibitor.

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Section: In Silico Evaluation Of N-benzylpiperidine Derivatives With ...supporting

confidence: 79%

Structure‐based design of new N‐benzyl‐piperidine derivatives as multitarget‐directed AChE/BuChE inhibitors for Alzheimer's disease

Conceição,

von Ranke,

Azevedo

et al. 2023

J of Cellular Biochemistry

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“…Studies targeting acetylcholinesterase inhibition started around 1980’s. Since then, a wide range of evidence shows that AChE inhibitors can improve cognitive function and slow down the progression of AD [ 11 , 23 , 24 ].…”

Section: Introductionmentioning

confidence: 99%

“…It was also suggested that potent PAS inhibitors that will hinder the entry to AChE gorge would prevent the A β peptide binding to AChE, and in this way help to slow down the progression of AD [ 25 , 26 ]. In this respect, dual binding AChE inhibitors which would interact with both CAS and PAS are emerging as an important research focus in AD treatment [ 6 , 11 ].…”

Section: Introductionmentioning

confidence: 99%

Proposing novel natural compounds against Alzheimer’s disease targeting acetylcholinesterase

2023

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Alzheimer’s disease (AD) is a neurodegenerative disorder considered as a global public health threat influencing many people. Despite the concerning rise in the affected population, there is still a shortage of potent and safe therapeutic agents. The aim of this research is to discover novel natural source molecules with high therapeutic effects, stability and less toxicity for the treatment of AD, specifically targeting acetylcholinesterase (AChE). This research can be divided into two steps: in silico search for molecules by systematic simulations and in vitro experimental validations. We identified five leading compounds, namely Queuine, Etoperidone, Thiamine, Ademetionine and Tetrahydrofolic acid by screening natural molecule database, conducting molecular docking and druggability evaluations. Stability of the complexes were investigated by Molecular Dynamics simulations and free energy calculations were conducted by Molecular Mechanics Generalized Born Surface Area method. All five complexes were stable within the binding catalytic site (CAS) of AChE, with the exception of Queuine which remains stable on the peripheral site (PAS). On the other hand Etoperidone both interacts with CAS and PAS sites showing dual binding properties. Binding free energy values of Queuine and Etoperidone were -71.9 and -91.0 kcal/mol respectively, being comparable to control molecules Galantamine (-71.3 kcal/mol) and Donepezil (-80.9 kcal/mol). Computational results were validated through in vitro experiments using the SH-SY5Y(neuroblastoma) cell line with Real Time Cell Analysis (RTCA) and cell viability assays. The results showed that the selected doses were effective with half inhibitory concentrations estimated to be: Queuine (IC50 = 70,90 μM), Etoperidone (IC50 = 712,80 μM), Thiamine (IC50 = 18780,34 μM), Galantamine (IC50 = 556,01 μM) and Donepezil (IC50 = 222,23 μM), respectively. The promising results for these molecules suggest the development of the next step in vivo animal testing and provide hope for natural therapeutic aids in the treatment of AD.

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“… 6 Furthermore, the promotion of rapid deposition of β-amyloid by AChE activities can also be prevented by AChE inhibitors, especially those with dual binding capacity. 7 …”

Section: Introductionmentioning

confidence: 99%

“…6 Furthermore, the promotion of rapid deposition of β-amyloid by AChE activities can also be prevented by AChE inhibitors, especially those with dual binding capacity. 7 The standard medical treatments for AD include cholinesterase inhibitors (AChEIs) and a partial N-methyl-Daspartate (NMDA) antagonist. Donepezil, Galantamine and Rivastigamine (AChEIs) as well as Memantine (NMDA antagonist) are for symptomatic relief and do not treat the underlying cause, nor halt the progression of the disease.…”

Section: Introductionmentioning

confidence: 99%

Revealing the Acetylcholinesterase Inhibitory Potential ofPhyllanthus amarusand Its Phytoconstituents: In Vitro and in Silico Approach

Faloye

Mahmud

Fakola

et al. 2022

Bioinform Biol Insights

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The inhibition of acetylcholinesterase plays a vital role in the treatment of Alzheimer disease. This study aimed to explore the acetylcholinesterase inhibition potential of Phyllanthus amarus and its phytoconstituents through an in vitro and in silico approach. The in vitro acetylcholinesterase inhibitory activity of P amarus was carried out, followed by the molecular docking studies of its phytoconstituents. The top-ranked molecules identified through molecular docking were subjected to molecular dynamics simulation (MDS) and density functional theory (DFT) studies. The results obtained revealed the methanolic extract of P amarus as a potent acetylcholinesterase inhibitor, while amarosterol A, hinokinin, β-sitosterol, stigmasterol and ellagic acid were identified as potential acetylcholinesterase inhibitors. The MDS and DFT results are in agreement with those obtained from the docking studies. Our findings suggest further studies on the hit molecules.

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An in silico approach to identify potential medicinal plants for treating Alzheimer disease: a case study with acetylcholinesterase

Cited by 11 publications

References 54 publications

Structure‐based design of new N‐benzyl‐piperidine derivatives as multitarget‐directed AChE/BuChE inhibitors for Alzheimer's disease

Structure‐based design of new N‐benzyl‐piperidine derivatives as multitarget‐directed AChE/BuChE inhibitors for Alzheimer's disease

Proposing novel natural compounds against Alzheimer’s disease targeting acetylcholinesterase

Revealing the Acetylcholinesterase Inhibitory Potential ofPhyllanthus amarusand Its Phytoconstituents: In Vitro and in Silico Approach

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