Identification of the first in silico-designed TREK1 antagonists that block channel currents dose dependently
- Title
- Identification of the first in silico-designed TREK1 antagonists that block channel currents dose dependently
- Author
- 민선준
- Keywords
- docking; homology model; novel antagonists; pharmacophore; TREK1; virtual screening
- Issue Date
- 2016-12
- Publisher
- WILEY-BLACKWELL
- Citation
- CHEMICAL BIOLOGY & DRUG DESIGN, v. 88, No. 6, Page. 807-819
- 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.
- URI
- https://onlinelibrary.wiley.com/doi/full/10.1111/cbdd.12810https://repository.hanyang.ac.kr/handle/20.500.11754/103083
- ISSN
- 1747-0277; 1747-0285
- DOI
- 10.1111/cbdd.12810
- Appears in Collections:
- COLLEGE OF SCIENCE AND CONVERGENCE TECHNOLOGY[E](과학기술융합대학) > CHEMICAL AND MOLECULAR ENGINEERING(화학분자공학과) > Articles
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