Key result
Drug design targeting an intermediate state allosteric pocket of the TREK-1 channel led to the identification of the TKIM compound as a new mechanistic inhibitor.
Why the study?
Whether intermediate states of ion channel gating are druggable remains underexplored.
The study demonstrates that intermediate states of ion channels can serve as druggable targets, identifying a novel allosteric inhibitor (TKIM) for the TREK-1 channel.
IM-state pockets may enable TREK-1 modulator design; leaves open experimental validation and clinical translation.
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.
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Ma et al. (2020) studied this question. TKIM compound was evaluated on Identification of an inhibitor targeting the intermediate state of TREK-1. Drug design targeting an intermediate state allosteric pocket of the TREK-1 channel led to the identification of the TKIM compound as a new mechanistic inhibitor.
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