ArticleCommunications biology2019
In silico re-engineering of a neurotransmitter to activate KCNQ potassium channels in an isoform-specific manner.
Article in Communications biology, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 6 papers.
What it found
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The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
6 citing papers in PubMed, 14 citations in OpenAlex.
- Glial KCNQ KNeuron · 2024Article
- KCNQ potassium channels modulate Wnt activity in gastro-oesophageal adenocarcinomas.Life science alliance · 2023Article
- KCNQ5 Potassium Channel Activation Underlies Vasodilation by Tea.Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology · 2021Article
- Isoform-Selective KCNA1 Potassium Channel Openers Built from Glycine.The Journal of pharmacology and experimental therapeutics · 2020Article
- Molecular Mechanisms and Structural Basis of Retigabine Analogues in Regulating KCNQ2 Channel.The Journal of membrane biology · 2020Article
- KCNQs: Ligand- and Voltage-Gated Potassium Channels.Frontiers in physiology · 2020Review
Corrections and comments
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Authors and funding
2 authors at 1 institution in 1 country.
Funding
Abstract
Voltage-gated potassium (Kv) channel dysfunction causes a variety of inherited disorders, but developing small molecules that activate Kv channels has proven challenging. We recently discovered that the inhibitory neurotransmitter γ-aminobutyric acid (GABA) directly activates Kv channels KCNQ3 and KCNQ5. Here, finding that inhibitory neurotransmitter glycine does not activate KCNQs, we re-engineered it in silico to introduce predicted KCNQ-opening properties, screened by in silico docking, then validated the hits in vitro. Attaching a fluorophenyl ring to glycine optimized its electrostatic potential, converting it to a low-nM affinity KCNQ channel activator. Repositioning the phenyl ring fluorine and/or adding a methylsulfonyl group increased the efficacy of the re-engineered glycines and switched their target KCNQs. Combining KCNQ2- and KCNQ3-specific glycine derivatives synergistically potentiated KCNQ2/3 activation by exploiting heteromeric channel composition. Thus, in silico optimization and docking, combined with functional screening of only three compounds, facilitated re-engineering of glycine to develop several potent KCNQ activators.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.