Identification of the First In Silico-designed TREK1 Antagonists that Block Channel Currents Dose-dependently

Abstract

TREK1 (Twik-RElated Potassium (K⁺) channel 1), though 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 6 active compounds. Validated Hypo1 and the most potent compound in the data set were employed as pharmacophore- and similarity-based virtual screening queries respectively. 33 hit compounds were tested for their ability to block TREK1 currents in HEK-293 transfected cells using whole-cell patch-clamp recording. 11 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 4.7 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.

This article is protected by copyright. All rights reserved.

In silico identification of novel TREK 1 antagonists.

from #MedicinebyAlexandrosSfakianakis via xlomafota13 on Inoreader http://ift.tt/293i2j4
via IFTTT