In Silico Identification of PAP-1 Binding Sites in the Kv1.2 Potassium Channel

Christian Jorgensen, Leonardo Darre, Kenno Vanommeslaeghe, Kiyoyuki Omoto, David Pryde, Carmen Domene*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

14 Citations (Scopus)

Abstract

Voltage-gated potassium channels of the Kv1 family play a crucial role in the generation and transmission of electrical signals in excitable cells affecting neuronal and cardiac activities. Small-molecule blockage of these channels has been proposed to occur via a cooperative mechanism involving two main blocking sites: the inner-pore site located below the selectivity filter, and a side-pocket cavity located between the pore and the voltage sensor. Using 0.5 mu s molecular dynamics simulation trajectories complemented by docking calculations, the potential binding sites of the PAP-1 (5-(4-phenoxybutoxy)psoralen) blocker to the crystal structure of Kv1.2 channel have been studied. The presence of both mentioned blocking sites at Kv1.2 is confirmed, adding evidence in favor of a cooperative channel blockage mechanism. These observations provide insight into drug modulation that will guide further developments of Kv inhibitors.

Original languageEnglish
Pages (from-to)1299-1307
Number of pages9
JournalMolecular Pharmaceutics
Volume12
Issue number4
Early online date3 Mar 2015
DOIs
Publication statusPublished - Apr 2015

Keywords

  • molecular dynamics simulations
  • docking ion channels
  • voltage gated ion channels
  • GENERAL FORCE-FIELD
  • GATED K+ CHANNELS
  • MOLECULAR-DYNAMICS
  • DRUG-BINDING
  • STRUCTURAL BASIS
  • BLOCK
  • ION
  • CHARMM
  • INHIBITORS
  • MECHANISM

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