Viswanath, Ambily Nath Indu Jung, Seo Yun Hwang, Eun Mi Park, Ki Duk Lim, Sang Min Min, Sun-Joon Cho, Yong Seo Pae, Ae Nim 2024-01-20T03:00:38Z 2024-01-20T03:00:38Z 2021-09-04 2016-12 1747-0277 https://pubs.kist.re.kr/handle/201004/123398 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 IC50 of 4.7m. 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. English WILEY DOMAIN POTASSIUM CHANNEL BACKGROUND K+ CHANNELS QUATERNARY AMMONIUM FUNCTIONAL EXPRESSION GENERAL-ANESTHESIA CRYSTAL-STRUCTURE GATING MECHANISM K-2P CHANNELS PORE INHIBITION Identification of the first in silico-designed TREK1 antagonists that block channel currents dose dependently Article 10.1111/cbdd.12810 1 CHEMICAL BIOLOGY & DRUG DESIGN, v.88, no.6, pp.807 - 819 CHEMICAL BIOLOGY & DRUG DESIGN 88 6 807 819 scie scopus 000387362800003 2-s2.0-84979788599 Biochemistry & Molecular Biology Chemistry, Medicinal Biochemistry & Molecular Biology Pharmacology & Pharmacy Article DOMAIN POTASSIUM CHANNEL BACKGROUND K+ CHANNELS QUATERNARY AMMONIUM FUNCTIONAL EXPRESSION GENERAL-ANESTHESIA CRYSTAL-STRUCTURE GATING MECHANISM K-2P CHANNELS PORE INHIBITION docking homology model novel antagonists pharmacophore TREK1 virtual screening