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

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

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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 μs 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
DOIs
Publication statusPublished - 1 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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