Identification of the first in silico-designed TREK1 antagonists that block channel currents dose dependently
- Authors
- 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
- Issue Date
- Dec-2016
- Publisher
- Blackwell
- Keywords
- docking; homology model; novel antagonists; pharmacophore; TREK1; virtual screening
- Citation
- Chemical Biology and Drug Design, v.88, no.6, pp.807 - 819
- Indexed
- SCIE
SCOPUS
- Journal Title
- Chemical Biology and Drug Design
- Volume
- 88
- Number
- 6
- Start Page
- 807
- End Page
- 819
- URI
- https://scholarworks.bwise.kr/erica/handle/2021.sw.erica/12168
- DOI
- 10.1111/cbdd.12810
- ISSN
- 1747-0277
- 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 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.
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