In silico re-engineering of a neurotransmitter to activate KCNQ potassium channels in an isoform-specific manner.
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.
['Manville|Rían W|RW|', 'Abbott|Geoffrey W|GW|']
D000818:Animals D003198:Computer Simulation D005998:Glycine D018684:Glycine Agents D051656:KCNQ Potassium Channels D051658:KCNQ2 Potassium Channel D051659:KCNQ3 Potassium Channel D008958:Models, Molecular D062105:Molecular Docking Simulation D015202:Protein Engineering D018009:Receptors, Glycine D055672:Static Electricity D058615:Synthetic Biology D029867:Xenopus Proteins D014982:Xenopus laevis
Neurophysiology Receptor pharmacology