ArticleJournal of the American Chemical Society2012
Generation of candidate ligands for nicotinic acetylcholine receptors via in situ click chemistry with a soluble acetylcholine binding protein template.
Article in Journal of the American Chemical Society, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 25 papers.
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Who cites it
25 citing papers in PubMed, 86 citations in OpenAlex.
- Click Reactions in Kinetic Target-Guided Synthesis: Progress in the Discovery of Inhibitors for Biological Targets.Methods and protocols · 2026Review
- Discovery of Boronic Acids-Based β-Lactamase Inhibitors Through In Situ Click Chemistry.International journal of molecular sciences · 2025Article
- Polymeric Micellar Nanocatalysts for CuAAC Click Reaction in Water.Langmuir : the ACS journal of surfaces and colloids · 2025Article
- The promise of molecular science in brain health. What breakthroughs are anticipated in the next 20 years?Cerebral circulation - cognition and behavior · 2024Article
- Review
- Shotgun Kinetic Target-Guided Synthesis Approach Enables the Discovery of Small-Molecule Inhibitors against Pathogenic Free-Living Amoeba Glucokinases.ACS infectious diseases · 2023Article
- Going beyond Binary: Rapid Identification of Protein-Protein Interaction Modulators Using a Multifragment Kinetic Target-Guided Synthesis Approach.Journal of medicinal chemistry · 2023Article
- Kinetic Target-Guided Synthesis of Small-Molecule G-Quadruplex Stabilizers.ChemistryOpen · 2020Article
- Expanded DNA and RNA Trinucleotide Repeats in Myotonic Dystrophy Type 1 Select Their Own Multitarget, Sequence-Selective Inhibitors.Biochemistry · 2020Article
- Sulfur(VI) Fluoride Exchange (SuFEx)-Enabled High-Throughput Medicinal Chemistry.Journal of the American Chemical Society · 2020Article
- Protein-Catalyzed Capture Agents.Chemical reviews · 2019Review
- Tailored therapeutics based on 1,2,3-1MedChemComm · 2019Review
- Methylpiperidinium Iodides as Novel Antagonists for α7 Nicotinic Acetylcholine Receptors.Frontiers in pharmacology · 2018Article
- In situ click chemistry generation of cyclooxygenase-2 inhibitors.Nature communications · 2017Article
- Interaction of three-finger proteins from snake venoms and from mammalian brain with the cys-loop receptors and their models.Doklady. Biochemistry and biophysics · 2016Article
- Ribosome-Templated Azide-Alkyne Cycloadditions: Synthesis of Potent Macrolide Antibiotics by In Situ Click Chemistry.Journal of the American Chemical Society · 2016Article
- Cholate-based synthesis of size-tunable cage compounds.The Journal of organic chemistry · 2015Article
- Real time ligand-induced motion mappings of AChBP and nAChR using X-ray single molecule tracking.Scientific reports · 2014Article
- A chemical epitope-targeting strategy for protein capture agents: the serine 474 epitope of the kinase Akt2.Angewandte Chemie (International ed. in English) · 2013Article
- Observation of the controlled assembly of preclick components in the in situ click chemistry generation of a chitinase inhibitor.Proceedings of the National Academy of Sciences of the United States of America · 2013Article
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Authors and funding
12 authors at 2 institutions in 1 country.
Funding
Abstract
Nicotinic acetylcholine receptors (nAChRs), which are responsible for mediating key physiological functions, are ubiquitous in the central and peripheral nervous systems. As members of the Cys loop ligand-gated ion channel family, neuronal nAChRs are pentameric, composed of various permutations of α (α2 to α10) and β (β2 to β4) subunits forming functional heteromeric or homomeric receptors. Diversity in nAChR subunit composition complicates the development of selective ligands for specific subtypes, since the five binding sites reside at the subunit interfaces. The acetylcholine binding protein (AChBP), a soluble extracellular domain homologue secreted by mollusks, serves as a general structural surrogate for the nAChRs. In this work, homomeric AChBPs from Lymnaea and Aplysia snails were used as in situ templates for the generation of novel and potent ligands that selectively bind to these proteins. The cycloaddition reaction between building-block azides and alkynes to form stable 1,2,3-triazoles was used to generate the leads. The extent of triazole formation on the AChBP template correlated with the affinity of the triazole product for the nicotinic ligand binding site. Instead of the in situ protein-templated azide-alkyne cycloaddition reaction occurring at a localized, sequestered enzyme active center as previously shown, we demonstrate that the in situ reaction can take place at the subunit interfaces of an oligomeric protein and can thus be used as a tool for identifying novel candidate nAChR ligands. The crystal structure of one of the in situ-formed triazole-AChBP complexes shows binding poses and molecular determinants of interactions predicted from structures of known agonists and antagonists. Hence, the click chemistry approach with an in situ template of a receptor provides a novel synthetic avenue for generating candidate agonists and antagonists for ligand-gated ion channels.
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