Discovery of an Inhibitor for the TREK‑1 Channel Targeting an Intermediate Transition State of Channel Gating

Modulators
can be designed to stabilize the inactive and active
states of ion channels, but whether intermediate (IM) states of channel
gating are druggable remains underexplored. In this study, using molecular
dynamics simulations of the TWIK-related potassium channel 1 (TREK-1)
channel, a two-pore domain potassium channel, we captured an IM state
during the transition from the down (inactive) state to the up (active-like)
state. The IM state contained a druggable allosteric pocket that was
not present in the down or up state. Drug design targeting the pocket
led to the identification of the TKIM compound as an
inhibitor of TREK-1. Using integrated methods, we verified that TKIM binds to the pocket of the IM state of TREK-1, which
differs from the binding of common inhibitors, which bind to channels
in the inactive state. Overall, this study identified an allosteric
ligand-binding site and a new mechanistic inhibitor for TREK-1, suggesting
that IM states of ion channels may be promising druggable targets
for use in discovering allosteric modulators.