可药性
变构调节
化学
门控
药物发现
离子通道
钾通道
生物物理学
过渡态模拟
结合位点
活动站点
生物化学
酶
受体
生物
基因
作者
Yuqin Ma,Qichao Luo,Jie Fu,Yanxin Che,Fei Guo,Lianghe Mei,Qiansen Zhang,Yang Li,Huaiyu Yang
标识
DOI:10.1021/acs.jmedchem.0c00842
摘要
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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