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Identification of the first in silico ‐designed TREK1 antagonists that block channel currents dose dependently
Author(s) -
Viswanath Ambily Nath Indu,
Jung Seo Yun,
Hwang Eun Mi,
Park Ki Duk,
Lim Sang Min,
Min SunJoon,
Cho Yong Seo,
Pae Ae Nim
Publication year - 2016
Publication title -
chemical biology and drug design
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.59
H-Index - 77
eISSN - 1747-0285
pISSN - 1747-0277
DOI - 10.1111/cbdd.12810
Subject(s) - pharmacophore , herg , in silico , virtual screening , chemistry , docking (animal) , homology modeling , stereochemistry , ligand (biochemistry) , potassium channel , combinatorial chemistry , computational biology , biochemistry , biophysics , biology , receptor , enzyme , medicine , nursing , gene
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‐((1 H ‐pyrrolo[2,3‐ b ]pyridin‐1‐yl)methyl)piperidin‐4‐ol heterocyclic core was the most potent one with an IC 50 of 4.7 μ m . 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.