Crystal structure of human acetylcholinesterase in complex with tacrine: Implications for drug discovery

Dileep, Kalarickal V.; Ihara, Kentaro; Mishima-Tsumagari, Chiemi; Kukimoto-Niino, Mutsuko; Yonemochi, Mayumi; Hanada, Kazuharu; Shirouzu, Mikako; Zhang, Kam Y. J.

doi:10.1016/j.ijbiomac.2022.05.009

Cited by 28 publications

(22 citation statements)

References 58 publications

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“…The potent compounds ( 4 , 11 , 15 for AChE; 4 , 9 , 15 for BChE; 8 , 10 , 11 for hCA I; 10 , 11 , 17 for hCA II; and 9 , 10 , 17 for α‐glucosidase) were studied for their possible binding interactions with the crystal structures of the AChE, BChE, hCA I, hCA II and α‐glucosidase by using molecular docking studies. For this purpose, the crystal structures of the AChE, BChE, hCA I and hCA II (PDB ID: 7XN1, 4BDS, 1AZM, 3HS4) were uploaded from the RCSB Protein Data Bank RCSB [52–55] . In this research, in vitro studies were conducted against α‐glucosidase enzyme from Saccharomyces cerevisiae.…”

Section: Methodsmentioning

confidence: 99%

Synthesis, Characterization, Bioactivity Impacts of New Anthranilic Acid Hydrazones Containing Aryl Sulfonate Moiety as Fenamate Isosteres

Tokalı¹,

Taslimi²,

Sadeghian³

et al. 2023

ChemistrySelect

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In this study, it was planned to synthesize new members of fenamate isosteres and investigate its effect on some metabolic enzymes such as Acetylcholinesterase, Butyrylcholinesterase, α‐Glucosidase, Carbonic andyhrase I–II. The target compounds were obtained from the reaction of N‐subtituted anthranilic hydrazides with sulfonylated aldehyde derivatives. The structures of the compounds were characterized using Fourier‐transform Infrared, Nuclear Magnetic Resonance, and High‐resolution Mass Spectroscopy. Compounds had potent inhibitory strength with Ki values in the range of 0.23±0.03–7.12±0.41 μM against carbonic anhydrase‐I and 0.13±0.01–6.21±0.52 μM against carbonic anhydrase‐II. Compounds inhibited acetycholinesterase and butyrylcholinesterase with the Ki values in the range of 42.73±15.80 nM–977.52±32.67 nM and 25.84±4.09 nM–261.36±34.05 nM, respectively. All compounds showed potent inhibitory activity against α‐glucosidase enzyme with IC50 value 1.51–23.51 nM, compared to the standard acarbose (64.53 nM). The orientation of binding of the synthesized compounds were further appraised by molecular docking studies, which reflects the importance of sulfonyl, furan, thiophene, and methoxy groups in protein‐ligand interaction. The docking results are complementary with the Ki values of compounds while the interaction pattern of the current compounds clearly indicates their structure‐activity relationship.

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Section: Methodsmentioning

confidence: 99%

Synthesis, Characterization, Bioactivity Impacts of New Anthranilic Acid Hydrazones Containing Aryl Sulfonate Moiety as Fenamate Isosteres

Tokalı¹,

Taslimi²,

Sadeghian³

et al. 2023

ChemistrySelect

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“…Moreover, the results suggest that an additional T‐shaped aromatic interaction with AChE_Tyr337 of the anionic subsite stabilizes the final orientation of W3_Trp3. The anionic subsite is a choline‐binding pocket that interacts with the charged quaternary amine of ACh and is the binding site of important hAChE inhibitors such as tacrine [19,20] . These interactions can be considered to account for the much higher inhibitory activity of the W3 derivative when compared to LL.…”

Section: Resultsmentioning

confidence: 99%

“…The anionic subsite is a choline-binding pocket that interacts with the charged quaternary amine of ACh and is the binding site of important hAChE inhibitors such as tacrine. [19,20] These interactions can be considered to account for the much higher inhibitory activity of the W3 derivative when compared to LL.…”

Section: Kinetics and Inhibitory Mechanism Of The Best Derivatives On...mentioning

confidence: 99%

Inhibition of Human Cholinesterases and in vitro β‐Amyloid Aggregation by Rationally Designed Peptides

Sanchís

Spinelli

Dias³

et al. 2023

ChemMedChem

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The multifactorial nature of Alzheimer's disease (AD) is now widely recognized, which has increased the interest in compounds that can address more than one AD-associated targets. Herein, we report the inhibitory activity on the human cholinesterases (acetylcholinesterase, hAChE and butyrylcholinesterase, hBChE) and on the AChE-induced β-amyloid peptide (Aβ) aggregation by a series of peptide derivatives designed by mutating aliphatic residues for aromatic ones. We identified peptide W3 (LGWVSKGKLL-NH 2 ) as an interesting scaffold for the development of new anti-AD multitarget-directed drugs. It showed the lowest IC 50 value against hAChE reported for a peptide (0.99 � 0.02 μM) and inhibited 94.2 % � 1.2 of AChEinduced Aβ aggregation at 10 μM. Furthermore, it inhibited hBChE (IC 50 , 15.44 � 0.91 μM), showed no in vivo toxicity in brine shrimp and had shown moderated radical scavenging and Fe 2 + chelating capabilities in previous studies. The results are in line with multiple reports showing the utility of the indole moiety for the development of cholinesterase inhibitors.

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“…Oxidative stress (OS) is an important feature of the early stages of AD, and the content of acetylcholine (ACh) in the brain is extremely important in learning and memory functions, which is negatively correlated with AChE activity (Dileep et al., 2022). The efficacy of peptides for AD prevention in vitro can be achieved by antioxidant and AChE inhibition tests (Lane et al., 2018).…”

Section: Evaluation Of Pdps For Ad Preventionmentioning

confidence: 99%

Plant‐derived peptides for the improvement of Alzheimer's disease: Production, functions, and mechanisms

Lin

Liu

et al. 2023

Food Frontiers

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Alzheimer's disease (AD) is a progressive neurodegenerative disease with an insidious onset that seriously affects human health. Plant-derived peptides have been found to hinder the development of AD pathologies, which is an excellent candidate for preventing AD. However, due to the excessively complicated pathogenesis of AD and the fact that most studies on the activity of plant-derived peptides are single and not deep enough, which restricted the development and application of plant-derived AD-prevention peptides (PADPs). This review summarized the currently available means of obtaining PADPs, in vitro and in vivo AD-prevention activity validation protocols, molecular pathways of PADPs, the structure-activity relationship between plant-derived peptides and AD-prevention activity, and some perspectives of current advanced technologies. This paper will help to develop the foundation for the production and exploitation of PADPs.

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Crystal structure of human acetylcholinesterase in complex with tacrine: Implications for drug discovery

Cited by 28 publications

References 58 publications

Synthesis, Characterization, Bioactivity Impacts of New Anthranilic Acid Hydrazones Containing Aryl Sulfonate Moiety as Fenamate Isosteres

Synthesis, Characterization, Bioactivity Impacts of New Anthranilic Acid Hydrazones Containing Aryl Sulfonate Moiety as Fenamate Isosteres

Inhibition of Human Cholinesterases and in vitro β‐Amyloid Aggregation by Rationally Designed Peptides

Plant‐derived peptides for the improvement of Alzheimer's disease: Production, functions, and mechanisms

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