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

Commun Biol. 2019 Nov 1:2:401. doi: 10.1038/s42003-019-0648-3. eCollection 2019.

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.

Keywords: Neurophysiology; Receptor pharmacology.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Computer Simulation
  • Glycine / analogs & derivatives
  • Glycine / chemistry
  • Glycine / metabolism
  • Glycine Agents / chemistry
  • Glycine Agents / metabolism
  • KCNQ Potassium Channels / chemistry*
  • KCNQ Potassium Channels / genetics
  • KCNQ Potassium Channels / metabolism*
  • KCNQ2 Potassium Channel / chemistry
  • KCNQ2 Potassium Channel / genetics
  • KCNQ2 Potassium Channel / metabolism
  • KCNQ3 Potassium Channel / chemistry
  • KCNQ3 Potassium Channel / genetics
  • KCNQ3 Potassium Channel / metabolism
  • Models, Molecular
  • Molecular Docking Simulation
  • Protein Engineering / methods
  • Receptors, Glycine / antagonists & inhibitors
  • Static Electricity
  • Synthetic Biology
  • Xenopus Proteins / chemistry
  • Xenopus Proteins / genetics
  • Xenopus Proteins / metabolism
  • Xenopus laevis / genetics
  • Xenopus laevis / metabolism

Substances

  • Glycine Agents
  • KCNQ Potassium Channels
  • KCNQ2 Potassium Channel
  • KCNQ3 Potassium Channel
  • Receptors, Glycine
  • Xenopus Proteins
  • Glycine