Discovery of new scaffolds from approved drugs as acetylcholinesterase inhibitors

RSC Advances ◽  
2015 ◽  
Vol 5 (110) ◽  
pp. 90288-90294 ◽  
Author(s):  
Yao Chen ◽  
Xiaoli Xu ◽  
Tingming Fu ◽  
Wei Li ◽  
Zongliang Liu ◽  
...  
Keyword(s):  
Acetylcholinesterase Inhibitors ◽  
Acetylcholinesterase Inhibition ◽  
Starting Point ◽  
Approved Drugs

Six approved drugs show acetylcholinesterase inhibition and can be the starting point in designing new acetylcholinesterase inhibitors (AChEIs).

scholarly journals Merged Tacrine-Based, Multitarget-Directed Acetylcholinesterase Inhibitors 2015–Present: Synthesis and Biological Activity

2020 ◽  
Vol 21 (17) ◽  
pp. 5965
Author(s):  
Todd J. Eckroat ◽  
Danielle L. Manross ◽  
Seth C. Cowan
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Biological Activity ◽  
Enzyme Inhibitor ◽  
Acetylcholinesterase Inhibitor ◽  
Acetylcholinesterase Inhibitors ◽  
New Drugs ◽  
Acetylcholinesterase Inhibition ◽  
Future Research ◽  
Starting Point

Acetylcholinesterase is an important biochemical enzyme in that it controls acetylcholine-mediated neuronal transmission in the central nervous system, contains a unique structure with two binding sites connected by a gorge region, and it has historically been the main pharmacological target for treatment of Alzheimer’s disease. Given the large projected increase in Alzheimer’s disease cases in the coming decades and its complex, multifactorial nature, new drugs that target multiple aspects of the disease at once are needed. Tacrine, the first acetylcholinesterase inhibitor used clinically but withdrawn due to hepatotoxicity concerns, remains an important starting point in research for the development of multitarget-directed acetylcholinesterase inhibitors. This review highlights tacrine-based, multitarget-directed acetylcholinesterase inhibitors published in the literature since 2015 with a specific focus on merged compounds (i.e., compounds where tacrine and a second pharmacophore show significant overlap in structure). The synthesis of these compounds from readily available starting materials is discussed, along with acetylcholinesterase inhibition data, relative to tacrine, and structure activity relationships. Where applicable, molecular modeling, to elucidate key enzyme-inhibitor interactions, and secondary biological activity is highlighted. Of the numerous compounds identified, there is a subset with promising preliminary screening results, which should inspire further development and future research in this field.

scholarly journals Development of a High-Throughput Screening Assay to Identify Inhibitors of the SARS-CoV-2 Guanine-N7-Methyltransferase Using RapidFire Mass Spectrometry

2021 ◽  
pp. 247255522110006
Author(s):  
Lesley-Anne Pearson ◽  
Charlotte J. Green ◽  
De Lin ◽  
Alain-Pierre Petit ◽  
David W. Gray ◽  
...  
Keyword(s):  
High Throughput ◽  
High Throughput Screening ◽  
Mutational Analysis ◽  
Nonstructural Protein ◽  
Translation Efficiency ◽  
Screening Assay ◽  
High Throughput Screening Assay ◽  
Starting Point ◽  
Approved Drugs ◽  
High Throughput Assay

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) represents a significant threat to human health. Despite its similarity to related coronaviruses, there are currently no specific treatments for COVID-19 infection, and therefore there is an urgent need to develop therapies for this and future coronavirus outbreaks. Formation of the cap at the 5′ end of viral RNA has been shown to help coronaviruses evade host defenses. Nonstructural protein 14 (nsp14) is responsible for N7-methylation of the cap guanosine in coronaviruses. This enzyme is highly conserved among coronaviruses and is a bifunctional protein with both N7-methyltransferase and 3′-5′ exonuclease activities that distinguish nsp14 from its human equivalent. Mutational analysis of SARS-CoV nsp14 highlighted its role in viral replication and translation efficiency of the viral genome. In this paper, we describe the characterization and development of a high-throughput assay for nsp14 utilizing RapidFire technology. The assay has been used to screen a library of 1771 Food and Drug Administration (FDA)-approved drugs. From this, we have validated nitazoxanide as a selective inhibitor of the methyltransferase activity of nsp14. Although modestly active, this compound could serve as a starting point for further optimization.

Synthesis and bioactivity of novel C2-glycosyl triazole derivatives as acetylcholinesterase inhibitors

2017 ◽  
Vol 23 (3) ◽  
pp. 231-236 ◽  
Author(s):  
Long Yin ◽  
Lei Wang ◽  
Xiu-Jian Liu ◽  
Feng-Chang Cheng ◽  
Da-Hua Shi ◽  
...  
Keyword(s):  
Aqueous Solution ◽  
Sodium Hydroxide ◽  
Acetylcholinesterase Inhibitors ◽  
Acetylcholinesterase Inhibition ◽  
Inhibition Activity ◽  
Triazole Derivatives ◽  
Inhibitory Activities ◽  
Ellman’S Method

AbstractNew C2-glycosyl triazole derivatives 6a–l were synthesized by cyclization of glycosyl acylthiosemicarbazides 5 in refluxing 3 N sodium hydroxide aqueous solution. Substrates 5 were obtained by the reaction of glycosyl isothiocyanate 3 with various hydrazides. The acetylcholinesterase (AChE) inhibitory activities of compounds 6 were tested by Ellman’s method. Compounds that exhibited over 85% inhibition were subsequently evaluated for the IC50 values. Compound 6f possesses the best acetylcholinesterase-inhibition activity with IC50 of 1.46±0.25 μg/mL.

scholarly journals High Throughput Virtual Screening to Discover Inhibitors of the Main Protease of the Coronavirus SARS-CoV-2

Molecules ◽  
2020 ◽  
Vol 25 (14) ◽  
pp. 3193 ◽  
Author(s):  
Olujide O. Olubiyi ◽  
Maryam Olagunju ◽  
Monika Keutmann ◽  
Jennifer Loschwitz ◽  
Birgit Strodel
Keyword(s):  
Natural Products ◽  
Kinase Inhibitors ◽  
Amino Acid Residues ◽  
Enzyme Dynamics ◽  
Hydrogen Bond Formation ◽  
Protease Enzyme ◽  
Main Protease ◽  
Starting Point ◽  
Approved Drugs

We use state-of-the-art computer-aided drug design (CADD) techniques to identify prospective inhibitors of the main protease enzyme, 3CLpro of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causing COVID-19. From our screening of over one million compounds including approved drugs, investigational drugs, natural products, and organic compounds, and a rescreening protocol incorporating enzyme dynamics via ensemble docking, we have been able to identify a range of prospective 3CLpro inhibitors. Importantly, some of the identified compounds had previously been reported to exhibit inhibitory activities against the 3CLpro enzyme of the closely related SARS-CoV virus. The top-ranking compounds are characterized by the presence of multiple bi- and monocyclic rings, many of them being heterocycles and aromatic, which are flexibly linked allowing the ligands to adapt to the geometry of the 3CLpro substrate site and involve a high amount of functional groups enabling hydrogen bond formation with surrounding amino acid residues, including the catalytic dyad residues H41 and C145. Among the top binding compounds we identified several tyrosine kinase inhibitors, which include a bioflavonoid, the group of natural products that binds best to 3CLpro. Another class of compounds that decently binds to the SARS-CoV-2 main protease are steroid hormones, which thus may be endogenous inhibitors and might provide an explanation for the age-dependent severity of COVID-19. Many of the compounds identified by our work show a considerably stronger binding than found for reference compounds with in vitro demonstrated 3CLpro inhibition and anticoronavirus activity. The compounds determined in this work thus represent a good starting point for the design of inhibitors of SARS-CoV-2 replication.

scholarly journals Synthesis, Biological Evaluation and Docking Studies of Chalcone and Flavone Analogs as Antioxidants and Acetylcholinesterase Inhibitors

2019 ◽  
Vol 9 (3) ◽  
pp. 410 ◽  
Author(s):  
Laura Díaz-Rubio ◽  
Rufina Hernández-Martínez ◽  
Arturo Estolano-Cobián ◽  
Daniel Chávez-Velasco ◽  
Ricardo Salazar-Aranda ◽  
...  
Keyword(s):  
Acetylcholinesterase Inhibitors ◽  
Acetylcholinesterase Activity ◽  
Biological Evaluation ◽  
Chemotherapeutic Agents ◽  
Acetylcholinesterase Inhibition ◽  
Ache Inhibitors ◽  
Antioxidant Agents ◽  
Wide Range ◽  
Β Carotene

Several oxidative processes are related to a wide range of human chronic and degenerative diseases, like Alzheimer’s disease, which also has been related to cholinergic processes. Therefore, search for new or improved antioxidant molecules with acetylcholinesterase activity is essential to offer alternative chemotherapeutic agents to support current drug therapies. A series of chalcone (2a–2k) and flavone (3a–3k) analogs were synthesized, characterized, and evaluated as acetylcholinesterase (AChE) inhibitors, and antioxidant agents using 1,1-diphenyl-2-picrylhydrazyl (DPPH•), 2-2′-azino-bis-(3-ethylbenzothiazoline-6-sulfonate) (ABTS•), and β-carotene/linoleic acid bleaching assay. Compounds more active were 3j and 2k in DPPH with EC50 of 1 × 10−8 and 5.4 × 10−3 μg/mL, respectively; 2g and 3i in ABTS (1.14 × 10−2 and 1.9 × 10−3 μg/mL); 2e, 2f, 3f, 2j, and 3j exceeded the α-tocopherol control in the β-carotene assay (98–99% of antioxidant activity). At acetylcholinesterase inhibition assay, flavones were more active than chalcones; the best results were compounds 2d and 3d (IC50 21.5 and 26.8 µg/mL, respectively), suggesting that the presence of the nitro group enhances the inhibitory activity. The docking of these two structures were made to understand their interactions with the AChE receptor. Although further in vivo testing must be performed, our results represent an important step towards the identification of improved antioxidants and acetylcholinesterase inhibitors.

scholarly journals In silico identification of anti-cancer compounds and plants from traditional Chinese medicine database

2016 ◽  
Vol 6 (1) ◽  
Author(s):  
Shao-Xing Dai ◽  
Wen-Xing Li ◽  
Fei-Fei Han ◽  
Yi-Cheng Guo ◽  
Jun-Juan Zheng ◽  
...  
Keyword(s):  
Chinese Medicine ◽  
Traditional Chinese Medicine ◽  
Cancer Drug ◽  
Cancer Drugs ◽  
Supportive Role ◽  
Starting Point ◽  
Anti Cancer ◽  
Approved Drugs ◽  
Alternative Resource

Abstract There is a constant demand to develop new, effective, and affordable anti-cancer drugs. The traditional Chinese medicine (TCM) is a valuable and alternative resource for identifying novel anti-cancer agents. In this study, we aim to identify the anti-cancer compounds and plants from the TCM database by using cheminformatics. We first predicted 5278 anti-cancer compounds from TCM database. The top 346 compounds were highly potent active in the 60 cell lines test. Similarity analysis revealed that 75% of the 5278 compounds are highly similar to the approved anti-cancer drugs. Based on the predicted anti-cancer compounds, we identified 57 anti-cancer plants by activity enrichment. The identified plants are widely distributed in 46 genera and 28 families, which broadens the scope of the anti-cancer drug screening. Finally, we constructed a network of predicted anti-cancer plants and approved drugs based on the above results. The network highlighted the supportive role of the predicted plant in the development of anti-cancer drug and suggested different molecular anti-cancer mechanisms of the plants. Our study suggests that the predicted compounds and plants from TCM database offer an attractive starting point and a broader scope to mine for potential anti-cancer agents.

Identification of Human Acetylcholinesterase Inhibitors from the Constituents of EGb761 by Modeling Docking and Molecular Dynamics Simulations

2018 ◽  
Vol 21 (1) ◽  
pp. 41-49 ◽  
Author(s):  
Lihu Zhang ◽  
Dongdong Li ◽  
Fuliang Cao ◽  
Wei Xiao ◽  
Linguo Zhao ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Molecular Docking ◽  
Serine Proteases ◽  
Colorimetric Method ◽  
Acetylcholinesterase Inhibitors ◽  
Docking Study ◽  
Molecular Docking Study ◽  
Ache Inhibitors ◽  
Starting Point

Aim and Objective: EGb761, a standardized and well-defined product extract of Ginkgo biloba leaves, has beneficial role in the treatment of multiple diseases, particularly Alzheimer's disease (AD). Identification of natural acetylcholinesterase (AChE) inhibitors from EGb761 would provide a novel therapeutic approach against the Alzheimer's disease. Material and Method: A series of 21 kinds of promising EGb761 compounds were selected, and subsequently evaluated for their potential ability to bind AChE enzyme by molecular docking and a deep analysis of protein surface pocket features. Results: Docking results indicated that these compounds can bind tightly with the active site of human AChE, with favorable distinct interactions around several important residues Asp74, Leu289, Phe295, Ser293, Tyr341, Trp286 and Val294 in the active pocket. Most EGB761 compounds could form the hydrogen bond interactions with the negatively charged Asp74 and Phe295 residues. Among these compounds, diosmetin is the one with the best-predicted docking score while three key hydrogen bonds can be formed between small molecule and corresponding residues of the binding site. Besides, other three compounds luteolin, apigenin, and isorhamnetin have better predicted docking scores towards AChE than other serine proteases, i.e Elastase, Tryptase, Factor XA, exhibiting specificity for AChE inhibition. The RMSD and MM-GBSA results from molecular dymamic simulations indicated that the docking pose of diosmetin-AChE complex displayed highly stable, which can be used for validating the accuracy of molecular docking study. Subsequently, the AChE inhibitory activities of these compounds were evaluated by the Ellman's colorimetric method. Conclusion: The obtained results revealed that all the four compounds exhibited modest AChE inhibitory activity, among which Diosmetin manifested remarkable anti-AChE activity, comparable with the reference compound, Physostigmine. It can be deduced that these EGB761 compounds can be regarded as a promising starting point for developing AChE inhibitors against AD.

scholarly journals Computational Drug Repositioning for Chagas Disease Using Protein-Ligand Interaction Profiling

2020 ◽  
Vol 21 (12) ◽  
pp. 4270 ◽  
Author(s):  
Alfredo Juárez-Saldivar ◽  
Michael Schroeder ◽  
Sebastian Salentin ◽  
V. Joachim Haupt ◽  
Emma Saavedra ◽  
...  
Keyword(s):  
Chagas Disease ◽  
Dihydrofolate Reductase ◽  
Drug Repositioning ◽  
Treatment Options ◽  
Ligand Interaction ◽  
Starting Point ◽  
Protein Ligand Interaction ◽  
New Treatment ◽  
Approved Drugs ◽  
Human Dihydrofolate Reductase

Chagas disease, caused by Trypanosoma cruzi (T. cruzi), affects nearly eight million people worldwide. There are currently only limited treatment options, which cause several side effects and have drug resistance. Thus, there is a great need for a novel, improved Chagas treatment. Bifunctional enzyme dihydrofolate reductase-thymidylate synthase (DHFR-TS) has emerged as a promising pharmacological target. Moreover, some human dihydrofolate reductase (HsDHFR) inhibitors such as trimetrexate also inhibit T. cruzi DHFR-TS (TcDHFR-TS). These compounds serve as a starting point and a reference in a screening campaign to search for new TcDHFR-TS inhibitors. In this paper, a novel virtual screening approach was developed that combines classical docking with protein-ligand interaction profiling to identify drug repositioning opportunities against T. cruzi infection. In this approach, some food and drug administration (FDA)-approved drugs that were predicted to bind with high affinity to TcDHFR-TS and whose predicted molecular interactions are conserved among known inhibitors were selected. Overall, ten putative TcDHFR-TS inhibitors were identified. These exhibited a similar interaction profile and a higher computed binding affinity, compared to trimetrexate. Nilotinib, glipizide, glyburide and gliquidone were tested on T. cruzi epimastigotes and showed growth inhibitory activity in the micromolar range. Therefore, these compounds could lead to the development of new treatment options for Chagas disease.

Synthesis and bioactivity of novel C2-glycosyl benzofuranylthiazoles derivatives as acetylcholinesterase inhibitors

2019 ◽  
Vol 43 (7-8) ◽  
pp. 257-261
Author(s):  
Lei Wang ◽  
Yu-Ran Wu ◽  
Shu-Ting Ren ◽  
Long Yin ◽  
You-Xian Wang ◽  
...  
Keyword(s):  
Inhibitory Concentration ◽  
Acetylcholinesterase Inhibitors ◽  
Acetylcholinesterase Inhibition ◽  
Inhibition Activity ◽  
Active Compounds ◽  
Inhibitory Activities ◽  
Ellman’S Method

A new series of C2-glycosyl benzofuranylthiazole derivatives was synthesised by the further cyclization of glycosyl thiourea and 2-(bromoacetyl)-benzofuran via Hantzsch’s method. The corresponding 2-(bromoacetyl)-benzofuran derivatives were obtained by the reaction from various salicylaldehydes, and the glycosyl thiourea was prepared through a series of steps from D-Glucosamine. The acetylcholinesterase-inhibitory activities of the products were tested by Ellman’s method. The most active compounds were subsequently evaluated for the 50% inhibitory concentration values. N-(1,3,4,6-tetra-O-benzyl-2-deoxy-β-D-glucopyranosyl)-4-(5-methoxy-benzofuran-2-yl)-1,3-thiazole-2-amine possessed the best acetylcholinesterase-inhibition activity with a 50% inhibitory concentration of 2.03 ± 0.26 μM.

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