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Commun Biol January 1, 2019; 2 401.

In silico re-engineering of a neurotransmitter to activate KCNQ potassium channels in an isoform-specific manner.

Manville RW , Abbott GW .

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.

PubMed ID: 31701029
PMC ID: PMC6825221
Article link: Commun Biol
Grant support: [+]

Species referenced: Xenopus
Genes referenced: glra1 kcnq1 kcnq2 kcnq3 kcnq4 kcnq5 mapt

Article Images: [+] show captions
References [+] :
Beacher, A case report: retigabine induced oral mucosal dyspigmentation of the hard palate. 2019, Pubmed