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Biomolecules
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Cholinesterase Research
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Cholinesterase Research

A special issue of Biomolecules (ISSN 2218-273X). This special issue belongs to the section "Cellular Biochemistry".

Deadline for manuscript submissions: closed (30 June 2021) | Viewed by 47978

Printed Edition Available!
A printed edition of this Special Issue is available here.

Special Issue Editors

Prof. Dr. Jan Korabecny

E-Mail Website
Guest Editor
Biomedical Research Center, University Hospital Hradec Kralove, Hradec Kralove, Czech Republic
Interests: Alzheimer's disease; acetylcholinesterase; butyrylcholinesterase; organic synthesis; anticancer drugs; kinase inhibitors; molecular modeling studies; medicinal chemistry; organophosphorus intoxication; chemical warfare agents; acetylcholinesterase reactivators; in silico studies
Special Issues, Collections and Topics in MDPI journals
Dr. Ondrej Soukup

E-Mail Website
Guest Editor
University Hospital Hradec Kralove, Hradec Kralove, Czech Republic
Interests: Alzheimer’s disease; acetylcholinesterase; butyrylcholinesterase; cholinesterase; drug development; organophosphate poisoning; nerve agents; oxime reactivators; toxicology; military pharmacy; drug delivery; in vitro testing; in vivo; toxicokinetics
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Cholinesterases are fundamental players in the peripheral and central nervous systems. These serine hydrolases are presented by two-membered families, namely acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). Under physiological conditions, AChE terminates the action of acetylcholine at synapses. The peculiar capacity of AChE also indicated, among others, its involvement in the differentiation of embryonic stem cells, neuritogenesis, cell adhesion, synaptogenesis, activation of dopamine neurons, amyloid beta fibre assembly, haematopoiesis and thrombopoiesis, or regulation of glutamate-mediated hippocampal activity. For AChE, its abrupt blockade has fatal consequences. This phenomenon is typical for a class of highly toxic compounds—nerve agents and pesticides, which can irreversibly inhibit enzymes. The role of BChE is still extensively discussed; it plays an important role in cholinergic mediation, it contributes to neurogenesis, and has detoxifying effect towards different xenobiotic drugs. It is also assumed that BChE overtakes the function of AChE in the case of malfunction.

Based on the abovementioned, both AChE and BChE are considered as highly relevant targets in the field of medicinal chemistry. For neurodegenerative disorders like Alzheimer’s disease, there is a strong consensus that AChE and BChE targeting by reversible inhibitors can, at least temporarily, alleviate the symptoms associated with the disorder, and enhance the cognitive performance of individuals. Other cholinesterase ligands, namely cholinesterase reactivators, typically endowed with strong nucleophilic function, can revert the irreversible action of organophosphorus compounds (nerve agents and pesticides). However, there are many other areas of research involving AChE and BChE, for example, pesticides; inflammation; and other neuronal disorders like Lewy body dementia, Parkinson’s disease, myasthenia gravis, and so on.

For this Special Issue of Biomolecules, “Cholinesterase Research”, we encourage the submission of review or original research articles that encompasses cholinesterase research at different levels, including structural aspects, drug design and development, in vitro biochemical studies, animal studies, and computational approaches, all devoted primarily to cholinesterases.

Prof. Dr. Jan Korabecny
Dr. Ondrej Soukup
Guest Editors

Manuscript Submission Information

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Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Biomolecules is an international peer-reviewed open access monthly journal published by MDPI.

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Keywords

  • acetylcholinesterase
  • butyrylcholinesterase
  • cholinesterase
  • drug design and development
  • nerve agents
  • oxime reactivators
  • antidotes
  • in silico approaches
  • in vitro studies
  • in vivo evaluation
  • medicinal chemistry
  • computational chemistry

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Published Papers (11 papers)

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Editorial

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4 pages, 177 KiB  
Editorial
Cholinesterase Research
by Jan Korabecny and Ondrej Soukup
Biomolecules 2021, 11(8), 1121; https://doi.org/10.3390/biom11081121 - 30 Jul 2021
Cited by 7 | Viewed by 2491
Abstract
Cholinesterases are fundamental players in the peripheral and central nervous systems [...] Full article
(This article belongs to the Special Issue Cholinesterase Research)

Research

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21 pages, 2990 KiB  
Article
Molecular Modeling Studies on the Multistep Reactivation Process of Organophosphate-Inhibited Acetylcholinesterase and Butyrylcholinesterase
by Jakub Jończyk, Jędrzej Kukułowicz, Kamil Łątka, Barbara Malawska, Young-Sik Jung, Kamil Musilek and Marek Bajda
Biomolecules 2021, 11(2), 169; https://doi.org/10.3390/biom11020169 - 27 Jan 2021
Cited by 6 | Viewed by 3097
Abstract
Poisoning with organophosphorus compounds used as pesticides or misused as chemical weapons remains a serious threat to human health and life. Their toxic effects result from irreversible blockade of the enzymes acetylcholinesterase and butyrylcholinesterase, which causes overstimulation of the cholinergic system and often [...] Read more.
Poisoning with organophosphorus compounds used as pesticides or misused as chemical weapons remains a serious threat to human health and life. Their toxic effects result from irreversible blockade of the enzymes acetylcholinesterase and butyrylcholinesterase, which causes overstimulation of the cholinergic system and often leads to serious injury or death. Treatment of organophosphorus poisoning involves, among other strategies, the administration of oxime compounds. Oximes reactivate cholinesterases by breaking the covalent bond between the serine residue from the enzyme active site and the phosphorus atom of the organophosphorus compound. Although the general mechanism of reactivation has been known for years, the exact molecular aspects determining the efficiency and selectivity of individual oximes are still not clear. This hinders the development of new active compounds. In our research, using relatively simple and widely available molecular docking methods, we investigated the reactivation of acetyl- and butyrylcholinesterase blocked by sarin and tabun. For the selected oximes, their binding modes at each step of the reactivation process were identified. Amino acids essential for effective reactivation and those responsible for the selectivity of individual oximes against inhibited acetyl- and butyrylcholinesterase were identified. This research broadens the knowledge about cholinesterase reactivation and demonstrates the usefulness of molecular docking in the study of this process. The presented observations and methods can be used in the future to support the search for new effective reactivators. Full article
(This article belongs to the Special Issue Cholinesterase Research)
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23 pages, 3875 KiB  
Article
Pursuing the Complexity of Alzheimer’s Disease: Discovery of Fluoren-9-Amines as Selective Butyrylcholinesterase Inhibitors and N-Methyl-d-Aspartate Receptor Antagonists
by Jan Konecny, Anna Misiachna, Martina Hrabinova, Lenka Pulkrabkova, Marketa Benkova, Lukas Prchal, Tomas Kucera, Tereza Kobrlova, Vladimir Finger, Marharyta Kolcheva, Stepan Kortus, Daniel Jun, Marian Valko, Martin Horak, Ondrej Soukup and Jan Korabecny
Biomolecules 2021, 11(1), 3; https://doi.org/10.3390/biom11010003 - 22 Dec 2020
Cited by 9 | Viewed by 3380
Abstract
Alzheimer’s disease (AD) is a complex disorder with unknown etiology. Currently, only symptomatic therapy of AD is available, comprising cholinesterase inhibitors and N-methyl-d-aspartate (NMDA) receptor antagonists. Drugs targeting only one pathological condition have generated only limited efficacy. Thus, combining two [...] Read more.
Alzheimer’s disease (AD) is a complex disorder with unknown etiology. Currently, only symptomatic therapy of AD is available, comprising cholinesterase inhibitors and N-methyl-d-aspartate (NMDA) receptor antagonists. Drugs targeting only one pathological condition have generated only limited efficacy. Thus, combining two or more therapeutic interventions into one molecule is believed to provide higher benefit for the treatment of AD. In the presented study, we designed, synthesized, and biologically evaluated 15 novel fluoren-9-amine derivatives. The in silico prediction suggested both the oral availability and permeation through the blood–brain barrier (BBB). An initial assessment of the biological profile included determination of the cholinesterase inhibition and NMDA receptor antagonism at the GluN1/GluN2A and GluN1/GluN2B subunits, along with a low cytotoxicity profile in the CHO-K1 cell line. Interestingly, compounds revealed a selective butyrylcholinesterase (BChE) inhibition pattern with antagonistic activity on the NMDARs. Their interaction with butyrylcholinesterase was elucidated by studying enzyme kinetics for compound 3c in tandem with the in silico docking simulation. The docking study showed the interaction of the tricyclic core of new derivatives with Trp82 within the anionic site of the enzyme in a similar way as the template drug tacrine. From the kinetic analysis, it is apparent that 3c is a competitive inhibitor of BChE. Full article
(This article belongs to the Special Issue Cholinesterase Research)
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19 pages, 4399 KiB  
Article
Impact of Sucrose as Osmolyte on Molecular Dynamics of Mouse Acetylcholinesterase
by Sofya V. Lushchekina, Gaetan Inidjel, Nicolas Martinez, Patrick Masson, Marie Trovaslet-Leroy, Florian Nachon, Michael Marek Koza, Tilo Seydel and Judith Peters
Biomolecules 2020, 10(12), 1664; https://doi.org/10.3390/biom10121664 - 12 Dec 2020
Cited by 11 | Viewed by 2629
Abstract
The enzyme model, mouse acetylcholinesterase, which exhibits its active site at the bottom of a narrow gorge, was investigated in the presence of different concentrations of sucrose to shed light on the protein and water dynamics in cholinesterases. The study was conducted by [...] Read more.
The enzyme model, mouse acetylcholinesterase, which exhibits its active site at the bottom of a narrow gorge, was investigated in the presence of different concentrations of sucrose to shed light on the protein and water dynamics in cholinesterases. The study was conducted by incoherent neutron scattering, giving access to molecular dynamics within the time scale of sub-nano to nanoseconds, in comparison with molecular dynamics simulations. With increasing sucrose concentration, we found non-linear effects, e.g., first a decrease in the dynamics at 5 wt% followed by a gain at 10 wt% sucrose. Direct comparisons with simulations permitted us to understand the following findings: at 5 wt%, sugar molecules interact with the protein surface through water molecules and damp the motions to reduce the overall protein mobility, although the motions inside the gorge are enhanced due to water depletion. When going to 10 wt% of sucrose, some water molecules at the protein surface are replaced by sugar molecules. By penetrating the protein surface, they disrupt some of the intra-protein contacts, and induce new ones, creating new pathways for correlated motions, and therefore, increasing the dynamics. This exhaustive study allowed for an explanation of the detail interactions leading to the observed non-linear behavior. Full article
(This article belongs to the Special Issue Cholinesterase Research)
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21 pages, 5013 KiB  
Article
1-(3-Tert-Butylphenyl)-2,2,2-Trifluoroethanone as a Potent Transition-State Analogue Slow-Binding Inhibitor of Human Acetylcholinesterase: Kinetic, MD and QM/MM Studies
by Irina V. Zueva, Sofya V. Lushchekina, Ian R. Pottie, Sultan Darvesh and Patrick Masson
Biomolecules 2020, 10(12), 1608; https://doi.org/10.3390/biom10121608 - 27 Nov 2020
Cited by 8 | Viewed by 2723
Abstract
Kinetic studies and molecular modeling of human acetylcholinesterase (AChE) inhibition by a fluorinated acetophenone derivative, 1-(3-tert-butylphenyl)-2,2,2-trifluoroethanone (TFK), were performed. Fast reversible inhibition of AChE by TFK is of competitive type with Ki = 5.15 nM. However, steady state of inhibition is reached [...] Read more.
Kinetic studies and molecular modeling of human acetylcholinesterase (AChE) inhibition by a fluorinated acetophenone derivative, 1-(3-tert-butylphenyl)-2,2,2-trifluoroethanone (TFK), were performed. Fast reversible inhibition of AChE by TFK is of competitive type with Ki = 5.15 nM. However, steady state of inhibition is reached slowly. Kinetic analysis showed that TFK is a slow-binding inhibitor (SBI) of type B with Ki* = 0.53 nM. Reversible binding of TFK provides a long residence time, τ = 20 min, on AChE. After binding, TFK acylates the active serine, forming an hemiketal. Then, disruption of hemiketal (deacylation) is slow. AChE recovers full activity in approximately 40 min. Molecular docking and MD simulations depicted the different steps. It was shown that TFK binds first to the peripheral anionic site. Then, subsequent slow induced-fit step enlarged the gorge, allowing tight adjustment into the catalytic active site. Modeling of interactions between TFK and AChE active site by QM/MM showed that the “isomerization” step of enzyme-inhibitor complex leads to a complex similar to substrate tetrahedral intermediate, a so-called “transition state analog”, followed by a labile covalent intermediate. SBIs of AChE show prolonged pharmacological efficacy. Thus, this fluoroalkylketone intended for neuroimaging, could be of interest in palliative therapy of Alzheimer’s disease and protection of central AChE against organophosphorus compounds. Full article
(This article belongs to the Special Issue Cholinesterase Research)
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22 pages, 3543 KiB  
Article
Potential Nutraceutical Properties of Leaves from Several Commonly Cultivated Plants
by Hafsa Amat-ur-Rasool, Fenella Symes, David Tooth, Larissa-Nele Schaffert, Ekramy Elmorsy, Mehboob Ahmed, Shahida Hasnain and Wayne G. Carter
Biomolecules 2020, 10(11), 1556; https://doi.org/10.3390/biom10111556 - 15 Nov 2020
Cited by 29 | Viewed by 5257
Abstract
Chronic dietary ingestion of suitable phytochemicals may assist with limiting or negating neurodegenerative decline. Current therapeutics used to treat Alzheimer disease elicit broad adverse drug reactions, and alternative sources of cholinesterase inhibitors (ChEIs) are required. Herein, we screened methanolic extracts from seven commonly [...] Read more.
Chronic dietary ingestion of suitable phytochemicals may assist with limiting or negating neurodegenerative decline. Current therapeutics used to treat Alzheimer disease elicit broad adverse drug reactions, and alternative sources of cholinesterase inhibitors (ChEIs) are required. Herein, we screened methanolic extracts from seven commonly cultivated plants for their nutraceutical potential; ability to inhibit acetylcholinesterase (AChE) and butyryl-cholinesterase (BuChE), and provision of antioxidant activity through their 2,2-diphenyl-1-picryl-hydrazyl-hydrate (DPPH) free radical scavenging capabilities. Potential neurotoxicity of plant extracts was examined via application to SHSY-5Y neuroblastoma cells and quantitation of cell viability. Methanolic extracts of Citrus limon (Lemon), Bombax ceiba (Red silk-cotton), Lawsonia inermis (Henna), Eucalyptus globulus (Eucalyptus), Ocimum basilicum (Basil), Citrus reticulata (Mandarin orange), and Mentha spicata (Spearmint) all displayed concentration-dependent inhibition of AChE and BuChE. The majority of extracts inhibited AChE and BuChE to near equipotency, with Henna and Eucalyptus extracts the two most potent ChEIs. All plant extracts were able to scavenge free radicals in a concentration-dependent manner, with Eucalyptus the most potent antioxidant. Toxicity of plant extracts to neuronal cells was concentration dependent, with Eucalyptus also the most toxic extract. Fractionation of plant extracts and analysis by mass spectrometry identified a number of plant polyphenols that might have contributed to the cholinesterase inhibition: 3-caffeoylquinic acid, methyl 4-caffeoylquinate, kaempferol-acetyl-glycoside, quercetin 3-rutinoside, quercetin-acetyl-glycoside, kaempferol 3-O-glucoside, and quercetin 3-O-glucoside. In silico molecular modeling of these polyphenols demonstrated their improved AChE and BuChE binding affinities compared to the current FDA-approved dual ChEI, galantamine. Collectively, all the plant extracts contained nutraceutical agents as antioxidants and ChEIs and, therefore, their chronic consumption may prove beneficial to combat the pathological deficits that accrue in Alzheimer disease. Full article
(This article belongs to the Special Issue Cholinesterase Research)
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25 pages, 4193 KiB  
Article
Evaluation of the Adverse Effects of Chronic Exposure to Donepezil (An Acetylcholinesterase Inhibitor) in Adult Zebrafish by Behavioral and Biochemical Assessments
by Gilbert Audira, Nguyen Thi Ngoc Anh, Bui Thi Ngoc Hieu, Nemi Malhotra, Petrus Siregar, Omar Villalobos, Oliver B. Villaflores, Tzong-Rong Ger, Jong-Chin Huang, Kelvin H.-C. Chen and Chung-Der Hsiao
Biomolecules 2020, 10(9), 1340; https://doi.org/10.3390/biom10091340 - 18 Sep 2020
Cited by 16 | Viewed by 5763
Abstract
Donepezil (DPZ) is an acetylcholinesterase inhibitor used for the clinical treatment of mild cognitive impairment. However, DPZ has been reported to have adverse effects, including causing abnormal cardiac rhythm, insomnia, vomiting, and muscle cramps. However, the existence of these effects in subjects without [...] Read more.
Donepezil (DPZ) is an acetylcholinesterase inhibitor used for the clinical treatment of mild cognitive impairment. However, DPZ has been reported to have adverse effects, including causing abnormal cardiac rhythm, insomnia, vomiting, and muscle cramps. However, the existence of these effects in subjects without Dementia is unknown. In this study, we use zebrafish to conduct a deeper analysis of the potential adverse effects of DPZ on the short-term memory and behaviors of normal zebrafish by performing multiple behavioral and biochemical assays. Adult zebrafish were exposed to 1 ppm and 2.5 ppm of DPZ. From the results, DPZ caused a slight improvement in the short-term memory of zebrafish and induced significant elevation in aggressiveness, while the novel tank and shoaling tests revealed anxiolytic-like behavior to be caused by DPZ. Furthermore, zebrafish circadian locomotor activity displayed a higher reduction of locomotion and abnormal movement orientation in both low- and high-dose groups, compared to the control group. Biomarker assays revealed that these alterations were associated with an elevation of oxytocin and a reduction of cortisol levels in the brain. Moreover, the significant increases in reactive oxygen species (ROS) and malondialdehyde (MDA) levels in muscle tissue suggest DPZ exposure induced muscle tissue oxidative stress and muscle weakness, which may underlie the locomotor activity impairment. In conclusion, we show, for the first time, that chronic waterborne exposure to DPZ can severely induce adverse effects on normal zebrafish in a dose-dependent manner. These unexpected adverse effects on behavioral alteration should be carefully addressed in future studies considering DPZ conducted on zebrafish or other animals. Full article
(This article belongs to the Special Issue Cholinesterase Research)
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14 pages, 4441 KiB  
Article
Postoperative Administration of the Acetylcholinesterase Inhibitor, Donepezil, Interferes with Bone Healing and Implant Osseointegration in a Rat Model
by Faez Saleh Al-Hamed, Ola M. Maria, Jeff Phan, Ahmed Al Subaie, Qiman Gao, Alaa Mansour, Lina Abu Nada, Imane Boukhatem, Osama A. Elkashty, Simon D. Tran, Marie Lordkipanidzé, Zahi Badran and Faleh Tamimi
Biomolecules 2020, 10(9), 1318; https://doi.org/10.3390/biom10091318 - 14 Sep 2020
Cited by 9 | Viewed by 3611
Abstract
Donepezil is an acetylcholinesterase inhibitor commonly used to treat mild to moderate Alzheimer’s disease. Its use has been associated with increased bone mass in humans and animals. However, the effect of postoperative administration of donepezil on bone healing remains unknown. Therefore, this study [...] Read more.
Donepezil is an acetylcholinesterase inhibitor commonly used to treat mild to moderate Alzheimer’s disease. Its use has been associated with increased bone mass in humans and animals. However, the effect of postoperative administration of donepezil on bone healing remains unknown. Therefore, this study aimed to assess the impact of postoperative injection of donepezil on bone healing, titanium-implant osseointegration, and soft tissue healing. Twenty-two Sprague-Dawley rats were randomly assigned to receive a daily dose of either donepezil (0.6 mg/kg) or saline as a control. In each rat, a uni-cortical defect was created in the right tibia metaphysis and a custom-made titanium implant was placed in the left tibiae. After two weeks, rats were euthanized, and their bones were analysed by Micro-CT and histology. The healing of bone defect and implant osseointegration in the rats treated with donepezil were significantly reduced compared to the saline-treated rats. Histomorphometric analysis showed lower immune cell infiltration in bone defects treated with donepezil compared to the saline-treated defects. On the other hand, the healing time of soft tissue wounds was significantly shorter in donepezil-treated rats compared to the controls. In conclusion, short-term administration of donepezil hinders bone healing whereas enhancing soft tissue healing. Full article
(This article belongs to the Special Issue Cholinesterase Research)
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22 pages, 4458 KiB  
Article
Efficacy Assessment of an Uncharged Reactivator of NOP-Inhibited Acetylcholinesterase Based on Tetrahydroacridine Pyridine-Aldoxime Hybrid in Mouse Compared to Pralidoxime
by André-Guilhem Calas, Anne-Sophie Hanak, Nina Jaffré, Aurélie Nervo, José Dias, Catherine Rousseau, Charlotte Courageux, Xavier Brazzolotto, Pascal Villa, Adeline Obrecht, Jean-François Goossens, Christophe Landry, Johan Hachani, Fabien Gosselet, Marie-Pierre Dehouck, Jagadeesh Yerri, Maria Kliachyna, Rachid Baati and Florian Nachon
Biomolecules 2020, 10(6), 858; https://doi.org/10.3390/biom10060858 - 4 Jun 2020
Cited by 13 | Viewed by 3253
Abstract
(1) Background: Human exposure to organophosphorus compounds employed as pesticides or as chemical warfare agents induces deleterious effects due to cholinesterase inhibition. One therapeutic approach is the reactivation of inhibited acetylcholinesterase by oximes. While currently available oximes are unable to reach the central [...] Read more.
(1) Background: Human exposure to organophosphorus compounds employed as pesticides or as chemical warfare agents induces deleterious effects due to cholinesterase inhibition. One therapeutic approach is the reactivation of inhibited acetylcholinesterase by oximes. While currently available oximes are unable to reach the central nervous system to reactivate cholinesterases or to display a wide spectrum of action against the variety of organophosphorus compounds, we aim to identify new reactivators without such drawbacks. (2) Methods: This study gathers an exhaustive work to assess in vitro and in vivo efficacy, and toxicity of a hybrid tetrahydroacridine pyridinaldoxime reactivator, KM297, compared to pralidoxime. (3) Results: Blood–brain barrier crossing assay carried out on a human in vitro model established that KM297 has an endothelial permeability coefficient twice that of pralidoxime. It also presents higher cytotoxicity, particularly on bone marrow-derived cells. Its strong cholinesterase inhibition potency seems to be correlated to its low protective efficacy in mice exposed to paraoxon. Ventilatory monitoring of KM297-treated mice by double-chamber plethysmography shows toxic effects at the selected therapeutic dose. This breathing assessment could help define the No Observed Adverse Effect Level (NOAEL) dose of new oximes which would have a maximum therapeutic effect without any toxic side effects. Full article
(This article belongs to the Special Issue Cholinesterase Research)
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17 pages, 1765 KiB  
Article
Amaryllidaceae Alkaloids of Belladine-Type from Narcissus pseudonarcissus cv. Carlton as New Selective Inhibitors of Butyrylcholinesterase
by Abdullah Al Mamun, Jana Maříková, Daniela Hulcová, Jiří Janoušek, Marcela Šafratová, Lucie Nováková, Tomáš Kučera, Martina Hrabinová, Jiří Kuneš, Jan Korábečný and Lucie Cahlíková
Biomolecules 2020, 10(5), 800; https://doi.org/10.3390/biom10050800 - 22 May 2020
Cited by 26 | Viewed by 5059
Abstract
Thirteen known (1–12 and 16) and three previously undescribed Amaryllidaceae alkaloids of belladine structural type, named carltonine A-C (13–15), were isolated from bulbs of Narcissus pseudonarcissus cv. Carlton (Amaryllidaceae) by standard chromatographic methods. Compounds isolated [...] Read more.
Thirteen known (1–12 and 16) and three previously undescribed Amaryllidaceae alkaloids of belladine structural type, named carltonine A-C (13–15), were isolated from bulbs of Narcissus pseudonarcissus cv. Carlton (Amaryllidaceae) by standard chromatographic methods. Compounds isolated in sufficient amounts, and not tested previously, were evaluated for their in vitro acetylcholinesterase (AChE; E.C. 3.1.1.7), butyrylcholinesterase (BuChE; E.C. 3.1.1.8) and prolyl oligopeptidase (POP; E.C. 3.4.21.26) inhibition activities. Significant human BuChE (hBUChE) inhibitory activity was demonstrated by newly described alkaloids carltonine A (13) and carltonine B (14) with IC50 values of 913 ± 20 nM and 31 ± 1 nM, respectively. Both compounds displayed a selective inhibition pattern for hBuChE with an outstanding selectivity profile over AChE inhibition, higher than 100. The in vitro data were further supported by in silico studies of the active alkaloids 13 and 14 in the active site of hBuChE. Full article
(This article belongs to the Special Issue Cholinesterase Research)
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Review

Jump to: Editorial, Research

35 pages, 3533 KiB  
Review
A Comprehensive Review of Cholinesterase Modeling and Simulation
by Danna De Boer, Nguyet Nguyen, Jia Mao, Jessica Moore and Eric J. Sorin
Biomolecules 2021, 11(4), 580; https://doi.org/10.3390/biom11040580 - 15 Apr 2021
Cited by 49 | Viewed by 8908
Abstract
The present article reviews published efforts to study acetylcholinesterase and butyrylcholinesterase structure and function using computer-based modeling and simulation techniques. Structures and models of both enzymes from various organisms, including rays, mice, and humans, are discussed to highlight key structural similarities in the [...] Read more.
The present article reviews published efforts to study acetylcholinesterase and butyrylcholinesterase structure and function using computer-based modeling and simulation techniques. Structures and models of both enzymes from various organisms, including rays, mice, and humans, are discussed to highlight key structural similarities in the active site gorges of the two enzymes, such as flexibility, binding site location, and function, as well as differences, such as gorge volume and binding site residue composition. Catalytic studies are also described, with an emphasis on the mechanism of acetylcholine hydrolysis by each enzyme and novel mutants that increase catalytic efficiency. The inhibitory activities of myriad compounds have been computationally assessed, primarily through Monte Carlo-based docking calculations and molecular dynamics simulations. Pharmaceutical compounds examined herein include FDA-approved therapeutics and their derivatives, as well as several other prescription drug derivatives. Cholinesterase interactions with both narcotics and organophosphate compounds are discussed, with the latter focusing primarily on molecular recognition studies of potential therapeutic value and on improving our understanding of the reactivation of cholinesterases that are bound to toxins. This review also explores the inhibitory properties of several other organic and biological moieties, as well as advancements in virtual screening methodologies with respect to these enzymes. Full article
(This article belongs to the Special Issue Cholinesterase Research)
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