ArticleThe Journal of membrane biology2020
Molecular Mechanisms and Structural Basis of Retigabine Analogues in Regulating KCNQ2 Channel.
Article in The Journal of membrane biology, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 10 papers.
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Who cites it
10 citing papers in PubMed, 20 citations in OpenAlex.
- Voltage-sensor conformational microenvironments encode isoform-selective ion channel activation.Proceedings of the National Academy of Sciences of the United States of America · 2026Article
- Molecular dynamics of the pathogenic KCNQ2 variant G256W reveal mechanisms of channel dysfunction in epileptic encephalopathy.bioRxiv : the preprint server for biology · 2025Article
- In Silico Methods for the Discovery of Kv7.2/7.3 Channels Modulators: A Comprehensive Review.Molecules (Basel, Switzerland) · 2024Review
- Dual regulation of Kv7.2/7.3 channels by long-chain n-alcohols.The Journal of general physiology · 2023Article
- Beyond Retigabine: Design, Synthesis, and Pharmacological Characterization of a Potent and Chemically Stable Neuronal Kv7 Channel Activator with Anticonvulsant Activity.Journal of medicinal chemistry · 2022Article
- High-throughput evaluation of epilepsy-associated KCNQ2 variants reveals functional and pharmacological heterogeneity.JCI insight · 2022Article
- A Review of Targeted Therapies for Monogenic Epilepsy Syndromes.Frontiers in neurology · 2022Review
- Chemical modulation of Kv7 potassium channels.RSC medicinal chemistry · 2021Review
- Molecular basis for ligand activation of the human KCNQ2 channel.Cell research · 2021Article
- KFrontiers in cellular neuroscience · 2020Review
Corrections and comments
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Authors and funding
12 authors at 2 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
KCNQ2 channel is one of the important members of potassium voltage-gated channel. KCNQ2 is closely related to neuronal excitatory diseases including epilepsy and neuropathic pain, and also acts as a drug target of the anti-epileptic drug, retigabine (RTG). In the past few decades, RTG has shown strong efficacy in the treatment of refractory epilepsy but has been withdrawn from clinical use due to its multiple adverse effects in clinical phase III trials. To overcome the drawbacks of RTG, several RTG analogues have been developed with different activation potency to KCNQ2. However, the detailed molecular mechanism by which these RTG analogues regulate KCNQ2 channel remains obscure. In this study, we used molecular simulations to analyse the interaction mode between the RTG analogues and KCNQ2, and to determine their molecular mechanism of action. Our data show that the van der Waals interactions, hydrophobic interactions, hydrogen bond, halogen bond, and π-π stacking work together to maintain the binding stability of the drugs in the binding pocket. On an atomic scale, the amide group in the carbamate and the amino group in the 2-aminophenyl moiety of RTG and RL648_81 are identified as key interaction sites. Our finding provides insight into the molecular mechanism by which KCNQ2 channels are regulated by RTG analogues. It also provides direct theoretical support for optimizing design of the KCNQ2 channel openers in the future, which will help treat refractory epilepsy caused by nerve excitability.
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