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

文献类型：期刊论文

作者Ma, Yuqin2,3; Luo, Qichao1,4,5; Fu, Jie4,5; Che, Yanxin2,3; Guo, Fei2,3; Mei, Lianghe6; Zhang, Qiansen4,5; Li, Yang2,3,7; Yang, Huaiyu4,5
刊名JOURNAL OF MEDICINAL CHEMISTRY
出版日期2020-10-08
卷号63期号:19页码:10972-10983
ISSN号0022-2623
DOI10.1021/acs.jmedchem.0c00842
通讯作者Luo, Qichao(lianqichao007@163.com) ; Li, Yang(liyang@simm.ac.cn) ; Yang, Huaiyu(hyyang@bio.ecnu.edu.cn)
英文摘要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.
WOS关键词2-PORE-DOMAIN POTASSIUM CHANNEL ; ENERGY LANDSCAPE ; HYDROGEN-BONDS ; K-2P CHANNELS ; BETA-HAIRPIN ; ION CHANNELS ; K+ CHANNELS ; MECHANISM ; DYNAMICS ; TRAAK
资助项目Personalized Medicines-Molecular Signature-based Drug Discovery and Development ; Strategic Priority Research Program of the Chinese Academy of Sciences[XDA12040220] ; National Science and Technology Major Project Key New Drug Creation and Manufacturing Program of China[2018ZX09711002] ; ECNU[44300-19311-542500/006] ; Fundamental Research Funds for the Central Universities ; State Key Laboratory of Bioorganic and Natural Products Chemistry ; ECNU Multifunctional Platform for Innovation[001]
WOS研究方向Pharmacology & Pharmacy
语种英语
WOS记录号WOS:000580558700019
出版者AMER CHEMICAL SOC
源URL[http://119.78.100.183/handle/2S10ELR8/296427]  
专题新药研究国家重点实验室
通讯作者Luo, Qichao; Li, Yang; Yang, Huaiyu
作者单位1.Jinan Univ, Guangdong Engn Technol Res Ctr Big Data Precis He, Big Data Decis Inst BDDI, Guangzhou 510632, Peoples R China
2.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China
3.Chinese Acad Sci, Shanghai Inst Mat Med, CAS Key Lab Receptor Res, Shanghai 201203, Peoples R China
4.East China Normal Univ, Inst Biomed Sci, Shanghai Key Lab Regulatory Biol, Shanghai 200241, Peoples R China
5.East China Normal Univ, Sch Life Sci, Shanghai 200241, Peoples R China
6.Chinese Acad Sci, Suzhou Inst Drug Innovat, Shanghai Inst Mat Med, Suzhou 215123, Jiangsu, Peoples R China
7.Univ Chinese Acad Sci, Beijing 100049, Peoples R China
推荐引用方式
GB/T 7714		 Ma, Yuqin,Luo, Qichao,Fu, Jie,et al. Discovery of an Inhibitor for the TREK-1 Channel Targeting an Intermediate Transition State of Channel Gating[J]. JOURNAL OF MEDICINAL CHEMISTRY,2020,63(19):10972-10983.
APA Ma, Yuqin.,Luo, Qichao.,Fu, Jie.,Che, Yanxin.,Guo, Fei.,...&Yang, Huaiyu.(2020).Discovery of an Inhibitor for the TREK-1 Channel Targeting an Intermediate Transition State of Channel Gating.JOURNAL OF MEDICINAL CHEMISTRY,63(19),10972-10983.
MLA Ma, Yuqin,et al."Discovery of an Inhibitor for the TREK-1 Channel Targeting an Intermediate Transition State of Channel Gating".JOURNAL OF MEDICINAL CHEMISTRY 63.19(2020):10972-10983.

入库方式： OAI收割

来源：上海药物研究所

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