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17 pages, 10745 KiB

Open AccessArticle

Cannabis Constituents and Acetylcholinesterase Interaction: Molecular Docking, In Vitro Studies and Association with CNR1 rs806368 and ACHE rs17228602

by Tiyyaba Furqan, Sidra Batool, Rabia Habib, Mamoona Shah, Huba Kalasz, Ferenc Darvas, Kamil Kuca, Eugenie Nepovimova, Sajida Batool and Syed M Nurulain

Biomolecules 2020, 10(5), 758; https://doi.org/10.3390/biom10050758 - 13 May 2020

Cited by 24 | Viewed by 4576

Abstract

The study documented here was aimed to find the molecular interactions of some of the cannabinoid constituents of cannabis with acetylcholinesterase (AChE). Molecular docking and LogP determination were performed to predict the AChE inhibitory effect and lipophilicity. AChE enzyme activity was measured in [...] Read more.

The study documented here was aimed to find the molecular interactions of some of the cannabinoid constituents of cannabis with acetylcholinesterase (AChE). Molecular docking and LogP determination were performed to predict the AChE inhibitory effect and lipophilicity. AChE enzyme activity was measured in the blood of cannabis addicted human subjects. Further, genetic predisposition to cannabis addiction was investigated by association analysis of cannabinoid receptor 1 (CNR1) single nucleotide polymorphism (SNP) rs806368 and ACHE rs17228602 using restriction fragment length polymorphism (RFLP) method. All the understudied cannabis constituents showed promising binding affinities with AChE and are lipophilic in nature. The AChE activity was observed to be indifferent in cannabis addicted and non-addicted healthy controls. There was no significant association with CNR1 SNP rs806368 and ACHE rs17228602. The study concludes that in silico prediction for individual biomolecules of cannabis is different from in vivo physiological action in human subjects when all are present together. However, for a deeper mechanistic insight into these interactions and association, multi-population studies are suggested. Further studies to explore the inhibitory potential of different cannabis constituents for intended AChE inhibitor-based drug are warranted. Full article

(This article belongs to the Special Issue Advances in Cholinesterases)

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8 pages, 2127 KiB

Open AccessFeature PaperArticle

Reactivation of VX-Inhibited Human Acetylcholinesterase by Deprotonated Pralidoxime. A Complementary Quantum Mechanical Study

by Jorge Alberto Valle da Silva, Ander Francisco Pereira, Steven R. LaPlante, Kamil Kuca, Teodorico Castro Ramalho and Tanos Celmar Costa França

Biomolecules 2020, 10(2), 192; https://doi.org/10.3390/biom10020192 - 27 Jan 2020

Cited by 11 | Viewed by 3859

Abstract

In the present work, we performed a complementary quantum mechanical (QM) study to describe the mechanism by which deprotonated pralidoxime (2-PAM) could reactivate human (Homo sapiens sapiens) acetylcholinesterase (HssAChE) inhibited by the nerve agent VX. Such a reaction is [...] Read more.

In the present work, we performed a complementary quantum mechanical (QM) study to describe the mechanism by which deprotonated pralidoxime (2-PAM) could reactivate human (Homo sapiens sapiens) acetylcholinesterase (HssAChE) inhibited by the nerve agent VX. Such a reaction is proposed to occur in subsequent addition–elimination steps, starting with a nucleophile bimolecular substitution (S_N2) mechanism through the formation of a trigonal bipyramidal transition state (TS). A near attack conformation (NAC), obtained in a former study using molecular mechanics (MM) calculations, was taken as a starting point for this project, where we described the possible formation of the TS. Together, this combined QM/MM study on AChE reactivation shows the feasibility of the reactivation occurring via attack of the deprotonated form of 2-PAM against the Ser203-VX adduct of HssAChE. Full article

(This article belongs to the Special Issue Advances in Cholinesterases)

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17 pages, 1466 KiB

Open AccessArticle

Biological Evaluation, Molecular Docking, and SAR Studies of Novel 2-(2,4-Dihydroxyphenyl)-1H- Benzimidazole Analogues

by Joanna Matysiak, Alicja Skrzypek, Monika Karpińska, Kamila Czarnecka, Paweł Szymański, Marek Bajda and Andrzej Niewiadomy

Biomolecules 2019, 9(12), 870; https://doi.org/10.3390/biom9120870 - 12 Dec 2019

Cited by 16 | Viewed by 3613

Abstract

In the present study, new 4-(1H-benzimidazol-2-yl)-benzene-1,3-diols, modified in both rings, have been synthesized and their efficacies as acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) inhibitors have been determined. The modified Ellman’s spectrophotometric method was applied for the biological evaluation. The compounds showed strong [...] Read more.

In the present study, new 4-(1H-benzimidazol-2-yl)-benzene-1,3-diols, modified in both rings, have been synthesized and their efficacies as acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) inhibitors have been determined. The modified Ellman’s spectrophotometric method was applied for the biological evaluation. The compounds showed strong (IC₅₀ 80–90 nM) AChE and moderate (IC₅₀ 5–0.2 µM) BuChE inhibition in vitro. Some compounds were effective toward AChE/BuChE, exhibiting high selectivity ratios versus BuChE, while the other compounds were active against both enzymes. The structure–activity relationships were discussed. The compounds inhibited also in vitro self-induced Aβ(1–42) aggregation and exhibited antioxidant properties. The docking simulations showed that the benzimidazoles under consideration interact mainly with the catalytic site of AChE and mimic the binding mode of tacrine. Full article

(This article belongs to the Special Issue Advances in Cholinesterases)

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13 pages, 2654 KiB

Open AccessArticle

In Vitro Evaluation of Neutral Aryloximes as Reactivators for Electrophorus eel Acetylcholinesterase Inhibited by Paraoxon

by Daniel A. S. Kitagawa, Samir F. de A. Cavalcante, Reuel L. de Paula, Rafael B. Rodrigues, Leandro B. Bernardo, Munique C. J. da Silva, Thiago N. da Silva, Wellington V. dos Santos, José M. Granjeiro, Joyce S. F. D. de Almeida, Marcos C. Barcellos, Ana Beatriz de A. Correa, Tanos C. C. França, Kamil Kuča and Alessandro B. C. Simas

Biomolecules 2019, 9(10), 583; https://doi.org/10.3390/biom9100583 - 8 Oct 2019

Cited by 15 | Viewed by 3828

Abstract

Casualties caused by organophosphorus pesticides are a burden for health systems in developing and poor countries. Such compounds are potent acetylcholinesterase irreversible inhibitors, and share the toxic profile with nerve agents. Pyridinium oximes are the only clinically available antidotes against poisoning by these [...] Read more.

Casualties caused by organophosphorus pesticides are a burden for health systems in developing and poor countries. Such compounds are potent acetylcholinesterase irreversible inhibitors, and share the toxic profile with nerve agents. Pyridinium oximes are the only clinically available antidotes against poisoning by these substances, but their poor penetration into the blood-brain barrier hampers the efficient enzyme reactivation at the central nervous system. In searching for structural factors that may be explored in future SAR studies, we evaluated neutral aryloximes as reactivators for paraoxon-inhibited Electrophorus eel acetylcholinesterase. Our findings may result into lead compounds, useful for development of more active compounds for emergencies and supportive care. Full article

(This article belongs to the Special Issue Advances in Cholinesterases)

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19 pages, 1286 KiB

Open AccessArticle

Exploring Structure-Activity Relationship in Tacrine-Squaramide Derivatives as Potent Cholinesterase Inhibitors

by Barbora Svobodova, Eva Mezeiova, Vendula Hepnarova, Martina Hrabinova, Lubica Muckova, Tereza Kobrlova, Daniel Jun, Ondrej Soukup, María Luisa Jimeno, José Marco-Contelles and Jan Korabecny

Biomolecules 2019, 9(8), 379; https://doi.org/10.3390/biom9080379 - 19 Aug 2019

Cited by 29 | Viewed by 5266

Abstract

Tacrine was the first drug to be approved for Alzheimer’s disease (AD) treatment, acting as a cholinesterase inhibitor. The neuropathological hallmarks of AD are amyloid-rich senile plaques, neurofibrillary tangles, and neuronal degeneration. The portfolio of currently approved drugs for AD includes acetylcholinesterase inhibitors [...] Read more.

Tacrine was the first drug to be approved for Alzheimer’s disease (AD) treatment, acting as a cholinesterase inhibitor. The neuropathological hallmarks of AD are amyloid-rich senile plaques, neurofibrillary tangles, and neuronal degeneration. The portfolio of currently approved drugs for AD includes acetylcholinesterase inhibitors (AChEIs) and N-methyl-d-aspartate (NMDA) receptor antagonist. Squaric acid is a versatile structural scaffold capable to be easily transformed into amide-bearing compounds that feature both hydrogen bond donor and acceptor groups with the possibility to create multiple interactions with complementary sites. Considering the relatively simple synthesis approach and other interesting properties (rigidity, aromatic character, H-bond formation) of squaramide motif, we combined this scaffold with different tacrine-based derivatives. In this study, we developed 21 novel dimers amalgamating squaric acid with either tacrine, 6-chlorotacrine or 7-methoxytacrine representing various AChEIs. All new derivatives were evaluated for their anti-cholinesterase activities, cytotoxicity using HepG2 cell line and screened to predict their ability to cross the blood-brain barrier. In this contribution, we also report in silico studies of the most potent AChE and BChE inhibitors in the active site of these enzymes. Full article

(This article belongs to the Special Issue Advances in Cholinesterases)

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Review

Jump to: Research

22 pages, 3087 KiB

Open AccessReview

Trends in the Recent Patent Literature on Cholinesterase Reactivators (2016–2019)

by Alexandre A. de Castro, Letícia C. Assis, Flávia V. Soares, Kamil Kuca, Daniel A. Polisel, Elaine F. F. da Cunha and Teodorico C. Ramalho

Biomolecules 2020, 10(3), 436; https://doi.org/10.3390/biom10030436 - 12 Mar 2020

Cited by 18 | Viewed by 4256

Abstract

Acetylcholinesterase (AChE) is the key enzyme responsible for deactivating the ACh neurotransmitter. Irreversible or prolonged inhibition of AChE, therefore, elevates synaptic ACh leading to serious central and peripheral adverse effects which fall under the cholinergic syndrome spectra. To combat the toxic effects of [...] Read more.

Acetylcholinesterase (AChE) is the key enzyme responsible for deactivating the ACh neurotransmitter. Irreversible or prolonged inhibition of AChE, therefore, elevates synaptic ACh leading to serious central and peripheral adverse effects which fall under the cholinergic syndrome spectra. To combat the toxic effects of some AChEI, such as organophosphorus (OP) nerve agents, many compounds with reactivator effects have been developed. Within the most outstanding reactivators, the substances denominated oximes stand out, showing good performance for reactivating AChE and restoring the normal synaptic acetylcholine (ACh) levels. This review was developed with the purpose of covering the new advances in AChE reactivation. Over the past years, researchers worldwide have made efforts to identify and develop novel active molecules. These researches have been moving farther into the search for novel agents that possess better effectiveness of reactivation and broad-spectrum reactivation against diverse OP agents. In addition, the discovery of ways to restore AChE in the aged form is also of great importance. This review will allow us to evaluate the major advances made in the discovery of new acetylcholinesterase reactivators by reviewing all patents published between 2016 and 2019. This is an important step in continuing this remarkable research so that new studies can begin. Full article

(This article belongs to the Special Issue Advances in Cholinesterases)

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22 pages, 3274 KiB

Open AccessReview

Acetylcholinesterase: The “Hub” for Neurodegenerative Diseases and Chemical Weapons Convention

by Samir F. de A. Cavalcante, Alessandro B. C. Simas, Marcos C. Barcellos, Victor G. M. de Oliveira, Roberto B. Sousa, Paulo A. de M. Cabral, Kamil Kuča and Tanos C. C. França

Biomolecules 2020, 10(3), 414; https://doi.org/10.3390/biom10030414 - 7 Mar 2020

Cited by 22 | Viewed by 7414

Abstract

This article describes acetylcholinesterase (AChE), an enzyme involved in parasympathetic neurotransmission, its activity, and how its inhibition can be pharmacologically useful for treating dementia, caused by Alzheimer’s disease, or as a warfare method due to the action of nerve agents. The chemical concepts [...] Read more.

This article describes acetylcholinesterase (AChE), an enzyme involved in parasympathetic neurotransmission, its activity, and how its inhibition can be pharmacologically useful for treating dementia, caused by Alzheimer’s disease, or as a warfare method due to the action of nerve agents. The chemical concepts related to the irreversible inhibition of AChE, its reactivation, and aging are discussed, along with a relationship to the current international legislation on chemical weapons. Full article

(This article belongs to the Special Issue Advances in Cholinesterases)

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17 pages, 654 KiB

Open AccessReview

Paraoxonase 3: Structure and Its Role in Pathophysiology of Coronary Artery Disease

by Kumari Priyanka, Surjit Singh and Kirandip Gill

Biomolecules 2019, 9(12), 817; https://doi.org/10.3390/biom9120817 - 3 Dec 2019

Cited by 20 | Viewed by 3692

Abstract

Spanning three decades in research, Paraoxonases (PON1) carried potential of dealing with neurotoxicity of organophosphates entering the circulation and preventing cholinergic crisis. In the past few years, the Paraoxonase multigene family (PON1, PON2, PON3) has been shown to play an important [...] Read more.

Spanning three decades in research, Paraoxonases (PON1) carried potential of dealing with neurotoxicity of organophosphates entering the circulation and preventing cholinergic crisis. In the past few years, the Paraoxonase multigene family (PON1, PON2, PON3) has been shown to play an important role in pathogenesis of cardiovascular disorders including coronary artery disease (CAD). The PON genes are clustered in tandem on the long arm of human chromosome 7 (q21, 22). All of them have been shown to act as antioxidants. Of them, PON3 is the least studied member as its exact physiological substrate is still not clear. This has further led to limitation in our understanding of its role in pathogenesis of CAD and development of the potential therapeutic agents which might modulate its activity, expression in circulation and tissues. In the present review, we discuss the structure and activity of human PON3 enzyme and its Single nucleotide variants that could potentially lead to new clinical strategies in prevention and treatment of CAD. Full article

(This article belongs to the Special Issue Advances in Cholinesterases)

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