Binding of resin acid derivatives to voltage-gated potassium channels
Voltage-gated ion channels are membrane proteins which control the flow of ions across the cell membrane. They are composed of four subunits that open and close their central ion-conducting pore in response to changes in the voltage across the membrane. The malfunction of these channels can cause hyperexcitability diseases such as epilepsy, cardiac arrhythmia and chronic pain. Polyunsaturated fatty acids (PUFAs) have been found to bind close to the voltage-sensor domain of voltage-gated K+ channels and cause the opening of the ion-conducting pore. However, the flexibility of PUFAs and the required high concentrations make them an unlikely drug target. Recently, however, highly potent resin acid derivatives were discovered, which activate the voltage-sensor of the voltage-gated Shaker K+ channel by an electrostatic mechanism, and could potentially be suitable drug targets in the treatment of hyperexcitability diseases. In this project, the focus is to study the specific binding of experimentally determined and highly potent resin acid derivatives, to the Shaker channel. We will be employing mainly docking methods in addition to molecular dynamics (MD) simulations to detail the specifics of the interactions between the compounds and the channel.