2. Academic Validation
  3. Discovery of an Inhibitor for the TREK-1 Channel Targeting an Intermediate Transition State of Channel Gating

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

  • J Med Chem. 2020 Oct 8;63(19):10972-10983. 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
Affiliations

Affiliations

  • 1 State Key Laboratory of Drug Research and CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China.
  • 2 Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, 500 Dongchuan Road, Shanghai 200241, China.
  • 3 Guangdong Engineering Technology Research Center for Big Data Precision Healthcare, Big Data Decision Institute (BDDI), Jinan University, 601 Huangpu Avenue West, Guangzhou 510632, China.
  • 4 Suzhou Institute of Drug Innovation, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 108 Yuxin Road, Suzhou, Jiangsu 215123, China.
  • 5 University of Chinese Academy of Sciences, No. 19A Yuquan Road, Beijing 100049, China.
PMID: 32877186 DOI: 10.1021/acs.jmedchem.0c00842
Abstract

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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