当前位置: X-MOL 学术J. Med. Chem. › 论文详情
Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)
Discovery of an Inhibitor for the TREK-1 Channel Targeting an Intermediate Transition State of Channel Gating.
Journal of Medicinal Chemistry ( IF 7.3 ) Pub Date : 2020-09-02 , DOI: 10.1021/acs.jmedchem.0c00842
Yuqin Ma 1 , Qichao Luo 2, 3 , Jie Fu 2 , Yanxin Che 1 , Fei Guo 1 , Lianghe Mei 4 , Qiansen Zhang 2 , Yang Li 1, 5 , Huaiyu Yang 2
Affiliation  

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.

中文翻译:

发现了针对TREK-1通道的抑制剂,该抑制剂靶向通道门控的中间过渡状态。

可以将调节器设计为稳定离子通道的非活动和活动状态,但是,通道门控的中间(IM)状态是否可药物化仍需进一步研究。在这项研究中,使用TWIK相关钾通道1(TREK-1)通道(两孔域钾通道)的分子动力学模拟,我们捕获了从向下(非活动)状态到向上(主动式)状态。IM状态包含向下或向上状态不存在的可药物化的变构口袋。针对口袋的药物设计导致将TKIM化合物鉴定为TREK-1抑制剂。使用集成方法,我们验证了TKIM结合TREK-1的IM状态的口袋,这不同于普通抑制剂的结合,后者在非活性状态下结合通道。总的来说,这项研究确定了TREK-1的变构配体结合位点和新的机械抑制剂,这表明离子通道的IM状态可能是用于发现变构调节剂的有希望的药物靶标。
更新日期:2020-10-08
down
wechat
bug