ArticleProceedings of the National Academy of Sciences of the United States of America2004
Freeze-frame inhibitor captures acetylcholinesterase in a unique conformation.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2004. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 67 papers.
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Who cites it
67 citing papers in PubMed, 329 citations in OpenAlex.
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- Acetylcholinesterase as a Multifunctional Target in Amyloid-Driven Neurodegeneration: From Dual-Site Inhibitors to Anti-Agregation Strategies.International journal of molecular sciences · 2025Review
- Design and development of an isatin-1,2,3-triazole hybrid analogue as a potent anti-inflammatory agent with enhanced efficacy and gene expression modulation.RSC advances · 2025Article
- Derivatives of Amodiaquine as Potent Human Cholinesterases Inhibitors: Implication for Treatment of Alzheimer's Disease.Molecules (Basel, Switzerland) · 2024Article
- Searching for potential acetylcholinesterase inhibitors: a combined approach of multi-step similarity search, machine learning and molecular dynamics simulations.Royal Society open science · 2024Article
- Evaluation of Anticholinesterase Activity of the Fungicides Mefentrifluconazole and Pyraclostrobin.International journal of molecular sciences · 2024Article
- Average Electron Density: A Quantitative Tool for Evaluating Non-Classical Bioisosteres of Amides.ACS omega · 2024Article
- Colorectal anticancer activity of a novel class of triazolic triarylmethane derivatives.RSC medicinal chemistry · 2024Article
- Fragment-based Drug Discovery Strategy and its Application to the Design of SARS-CoV-2 Main Protease Inhibitor.Current medicinal chemistry · 2024Review
- New Thienobenzo/Naphtho-Triazoles as Butyrylcholinesterase Inhibitors: Design, Synthesis and Computational Study.International journal of molecular sciences · 2023Article
- Identifying Possible AChE Inhibitors from Drug-like Molecules via Machine Learning and Experimental Studies.ACS omega · 2022Article
- Design, synthesis, and biological evaluation of new thalidomide-donepezil hybrids as neuroprotective agents targeting cholinesterases and neuroinflammation.RSC medicinal chemistry · 2022Article
- ELIXIR-A: An Interactive Visualization Tool for Multi-Target Pharmacophore Refinement.ACS omega · 2022Article
- Discovery and In Vivo Proof of Concept of a Highly Potent Dual Inhibitor of Soluble Epoxide Hydrolase and Acetylcholinesterase for the Treatment of Alzheimer's Disease.Journal of medicinal chemistry · 2022Article
- A New Class of Bi- and Trifunctional Sugar Oximes as Antidotes against Organophosphorus Poisoning.Journal of medicinal chemistry · 2022Article
- Novel 1,2,3-Triazole-Coumarin Hybrid Glycosides and Their Tetrazolyl Analogues: Design, Anticancer Evaluation and Molecular Docking Targeting EGFR, VEGFR-2 and CDK-2.Molecules (Basel, Switzerland) · 2022Article
- In Vitro and In Vivo Antiviral Studies of New Heteroannulated 1,2,3-Triazole Glycosides Targeting the Neuraminidase of Influenza A Viruses.Pharmaceuticals (Basel, Switzerland) · 2022Article
- Click chemistry based synthesis, cytotoxic activity and molecular docking of novel triazole-thienopyrimidine hybrid glycosides targeting EGFR.Journal of enzyme inhibition and medicinal chemistry · 2021Article
- Development of versatile and potent monoquaternary reactivators of acetylcholinesterase.Archives of toxicology · 2021Article
7 more citing papers are in PubMed but not listed here.
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Authors and funding
6 authors at 4 institutions in 2 countries.
Funding
Abstract
The 1,3-dipolar cycloaddition reaction between unactivated azides and acetylenes proceeds exceedingly slowly at room temperature. However, considerable rate acceleration is observed when this reaction occurs inside the active center gorge of acetylcholinesterase (AChE) between certain azide and acetylene reactants, attached via methylene chains to specific inhibitor moieties selective for the active center and peripheral site of the enzyme. AChE catalyzes the formation of its own inhibitor in a highly selective fashion: only a single syn1-triazole regioisomer with defined substitution positions and linker distances is generated from a series of reagent combinations. Inhibition measurements revealed this syn1-triazole isomer to be the highest affinity reversible organic inhibitor of AChE with association rate constants near the diffusion limit. The corresponding anti1 isomer, not formed by the enzyme, proved to be a respectable but weaker inhibitor. The crystal structures of the syn1- and anti1-mouse AChE complexes at 2.45- to 2.65-A resolution reveal not only substantial binding contributions from the triazole moieties, but also that binding of the syn1 isomer induces large and unprecedented enzyme conformational changes not observed in the anti1 complex nor predicted from structures of the apoenzyme and complexes with the precursor reactants. Hence, the freeze-frame reaction offers both a strategically original approach for drug discovery and a means for kinetically controlled capture, as a high-affinity complex between the enzyme and its self-created inhibitor, of a highly reactive minor abundance conformer of a fluctuating protein template.
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