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 language | English |
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Pages (from-to) | 1299-1307 |
Number of pages | 9 |
Journal | Molecular Pharmaceutics |
Volume | 12 |
Issue number | 4 |
Early online date | 3 Mar 2015 |
DOIs | |
Publication status | Published - 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