title: Identification of the first in silico-designed TREK1 antagonists that block channel currents dose dependently.
abstract: TREK1 (Twik-RElated Potassium (K+) channel 1), although a well-characterized target for several neuropsychiatric disorders, underwent very few explorations for prototypic inhibitors. This study aimed to find diverse chemotypes by an in silico means. Homology-built TREK1 on docking with high-affinity quaternary ammonium compounds (QAs) corroborated the previous findings by recreating the binding mode with proximally positioned key residues: Thr157, Thr266, Ile182, Leu189, and Leu304. Physical interactions between TREK1 and known antagonists were modeled to compensate the lack of ligand-bound protein crystal structures. A common feature hypothesis (Hypo1) was deduced from the chemical features of six active compounds. Validated Hypo1 and the most potent compound in the data set were employed as pharmacophore- and similarity-based virtual screening queries, respectively. Thirty-three hit compounds were tested for their ability to block TREK1 currents in HEK-293-transfected cells using whole-cell patch-clamp recording. Eleven candidates displayed dose-dependent inhibition of channel currents; among these, NC30 possessing a 4-((1H-pyrrolo[2,3-b]pyridin-1-yl)methyl)piperidin-4-ol heterocyclic core was the most potent one with an IC50of 4.7 μm. These results form a rational basis to design future drugs, and this is the first report of novel TREK1 antagonists delineated by a synergistic application of structure- and ligand-based approaches.
authors.affiliation: Convergence Research Center for Diagnosis, Treatment and Care System of Dementia, Korea Institute of Science and Technology, Seoul, Korea.|Department of Biological Chemistry, Korea University of Science and Technology, Daejeon, Korea.
authors.forename: Ambily Nath Indu
authors.initials: AN
authors.lastname: Viswanath
authors.affiliation: Convergence Research Center for Diagnosis, Treatment and Care System of Dementia, Korea Institute of Science and Technology, Seoul, Korea.
authors.forename: Seo Yun
authors.initials: SY
authors.lastname: Jung
authors.affiliation: Department of Biological Chemistry, Korea University of Science and Technology, Daejeon, Korea.|Center for Functional Connectomics, Korea Institute of Science and Technology, Seoul, Korea.
authors.forename: Eun Mi
authors.initials: EM
authors.lastname: Hwang
authors.affiliation: Convergence Research Center for Diagnosis, Treatment and Care System of Dementia, Korea Institute of Science and Technology, Seoul, Korea.|Department of Biological Chemistry, Korea University of Science and Technology, Daejeon, Korea.
authors.forename: Ki Duk
authors.initials: KD
authors.lastname: Park
authors.affiliation: Center for Neuro-Medicine, Korea Institute of Science and Technology, Seoul, Korea.
authors.forename: Sang Min
authors.initials: SM
authors.lastname: Lim
authors.affiliation: Department of Applied Chemistry, Hanyang University ERICA Campus, Sangnok-gu, Ansan, Gyeonggi-do, Korea.
authors.forename: Sun-Joon
authors.initials: SJ
authors.lastname: Min
authors.affiliation: Center for Neuro-Medicine, Korea Institute of Science and Technology, Seoul, Korea.
authors.forename: Yong Seo
authors.initials: YS
authors.lastname: Cho
authors.affiliation: Convergence Research Center for Diagnosis, Treatment and Care System of Dementia, Korea Institute of Science and Technology, Seoul, Korea. anpae@kist.re.kr.|Department of Biological Chemistry, Korea University of Science and Technology, Daejeon, Korea. anpae@kist.re.kr.
authors.forename: Ae Nim
authors.initials: AN
authors.lastname: Pae
mesh_terms: D000818:Animals; D003198:Computer Simulation; D018360:Crystallography, X-Ray; D004305:Dose-Response Relationship, Drug; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D062105:Molecular Docking Simulation; D024683:Potassium Channels, Tandem Pore Domain / Q000037:antagonists & inhibitors* / Q000235:genetics
chemical_list: D024683:Potassium Channels, Tandem Pore Domain; C103742:potassium channel protein TREK-1
keywords: TREK1; docking; homology model; novel antagonists; pharmacophore; virtual screening