The Peripheral Anionic Site of Acetylcholinesterase: Structure, Functions and Potential Role in Rational Drug Design

Johnson, Glynis; Moore, Samuel W.

doi:10.2174/138161206775193127

Cited by 249 publications

(149 citation statements)

References 102 publications

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“…The aromatic site contains loops and it has good conformational flexibility. Tyr 70, Asp 72, Tyr 121, Trp 279 and Tyr 334 amino acids residues are the most significant residues in the peripheral anionic site 48 . As described in the following chapters, the peripheral anionic site is a target for a number of toxins and also promising drugs 49,50 .…”

Section: Acetylcholinesterasementioning

confidence: 99%

Cholinesterases, a Target of Pharmacology and Toxicology

Pohanka¹

2011

Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub

325

219

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Background. Cholinesterases are a group of serine hydrolases that split the neurotransmitter acetylcholine (ACh) and terminate its action. Of the two types, butyrylcholinesterase and acetylcholinesterase (AChE), AChE plays the key role in ending cholinergic neurotransmission. Cholinesterase inhibitors are substances, either natural or man-made that interfere with the break-down of ACh and prolong its action. Hence their relevance to toxicology and pharmacology.Methods and Results. The present review summarizes current knowledge of the cholinesterases and their inhibition. Particular attention is paid to the toxicology and pharmacology of cholinesterase-related inhibitors such as nerve agents (e.g. sarin, soman, tabun, VX), pesticides (e.g. paraoxon, parathion, malathion, malaoxon, carbofuran), selected plants and fungal secondary metabolites (e.g. aflatoxins), drugs for Alzheimer's disease (e.g. huperzine, metrifonate, tacrine, donepezil) and Myasthenia gravis (e.g. pyridostigmine) treatment and other compounds (propidium, ethidium, decamethonium).Conclusions. The crucial role of the cholinesterases in neural transmission makes them a primary target of a large number of cholinesterase-inhibiting drugs and toxins. In pharmacology, this has relevance to the treatment of neurodegenerative disorders.

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Section: Acetylcholinesterasementioning

confidence: 99%

Cholinesterases, a Target of Pharmacology and Toxicology

Pohanka¹

2011

Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub

325

219

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“…The potential of a naphthoquinone substructure in the chemical space related to neurodegenerative diseases such as Alzheimer's were proved in recent works (11,12). Naphtoquinone as an anti-amyloid preferential motif, interact with several amyloid proteins, owing to its capability to form favorable π-stacking and hydrogen bond interactions.…”

Section: Introductionmentioning

confidence: 99%

“…This site of AChE lies at the entrance to the active site pharynx. It is composed of 5 residues (Tyr 72, Asp74, Tyr124, Trp286, and Tyr 341) as well as a number of surface loops, conferring a high degree of conformational flexibility on the area (12).…”

Section: Introductionmentioning

confidence: 99%

Molecular Docking and PLIF Studies of Novel Tacrine-Naphtoquinone Hybrids Based on Multi-Target-Directed Ligand Approach for Alzheimer’s Disease

Fereidoonnezhad

Mostoufi

Zali

et al. 2017

Jundishapur J Nat Pharm Prod

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Alzheimer's disease (AD), the most typical type of dementia and memory loss, is a complicated and progressive neurodegenerative disorder. Due to the multi-factorial etiology of AD, the multi-target-directed ligand (MTDL) approach can be a potential method in seeking new drug candidates for this disease. In this study, over 200 tacrine-naphtoquinone hybrids have been designed and their drug-likeness, molecular docking, and descriptor analysis were conducted to find out a drug candidate with less toxicity and better binding affinity than tacrine. The Docking analysis was conducted using human acetylcholineesterase (1ACJ), human butyrylcholineesterase (4BDS), and β-secretase (BACE1) (1w51) enzymes using Autodock 4.2 and Vina. Promising results were obtained on the types of interactions. Based on molecular docking on 3 targets as well as protein ligand interaction fingerprint (PLIF) studies, the compounds with better results were introduced as good candidates for synthesis. The validity of docking protocols was confirmed using a set of familiar active ligands and decoys on these targets by means of 2 known statistical metrics such as the receiver-operating characteristic (ROC) and Enrichment Factor (EF). Structure activity relationship (SAR) studies, in these class of compounds, show that the hydroxyethylamine, as a linker, is an essential group to improving binding site to AChE and BACE-1 targets.

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“…The PAS consists of five residues (Tyr72, Asp74, Tyr124, Trp286 and Tyr337) involved in the allosteric modulation of catalysis at the active site and is the target of various anti-cholinesterase drugs. It is also implicated in a number of non-classical functions, in particular, amyloid deposition, cell adhesion and neurite outgrowth 7 . A gorge, surrounded by aromatic amino acidic residues and with a length of about 20 Å , connects the PAS to the active site 8 .…”

Section: Introductionmentioning

confidence: 99%

NewN,N-dimethylcarbamate inhibitors of acetylcholinesterase: design synthesis and biological evaluation

Vita

Pandolfi

Ornano

et al. 2016

Journal of Enzyme Inhibition and Medicinal Chemistry

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A series of N,N-dimethylcarbamates containing a N,N-dibenzylamino moiety was synthesized and tested to evaluate their ability to inhibit Acetylcholinesterase (AChE). The most active compounds 4 and 8, showed 85 and 69% of inhibition at 50 mM, respectively. Furthermore, some basic SAR rules were outlined: an alkyl linker of six methylene units is the best spacer between the carbamoyl and dibenzylamino moieties; electron-withdrawal substituents on aromatics rings of the dibenzylamino group reduce the inhibitory power. Compound 4 produces a slow onset inhibition of AChE and this is not due to the carbamoylation of the enzyme, as demonstrated by the time-dependent inhibition assay of AChE with compound 4 and by MALDI-TOF MS analysis of trypsinized AChE inhibited by compound 4. Instead, compound 4 could act as a slow-binding inhibitor of AChE, probably because of its high conformational freedom due to the linear alkyl chain.

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The Peripheral Anionic Site of Acetylcholinesterase: Structure, Functions and Potential Role in Rational Drug Design

Cited by 249 publications

References 102 publications

Cholinesterases, a Target of Pharmacology and Toxicology

Cholinesterases, a Target of Pharmacology and Toxicology

Molecular Docking and PLIF Studies of Novel Tacrine-Naphtoquinone Hybrids Based on Multi-Target-Directed Ligand Approach for Alzheimer’s Disease

NewN,N-dimethylcarbamate inhibitors of acetylcholinesterase: design synthesis and biological evaluation

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