Identification of the first in silico-designed TREK1 antagonists that block channel currents dose dependently

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• 作者：Ambily Nath Indu Viswanath ; Seo Yun Jung ; Eun Mi Hwang ; Ki Duk Park ; Sang Min Lim ; Sun-Joon Min ; Yong Seo Cho and Ae Nim Pae
• 刊名：Chemical Biology & Drug Design
• 出版年：2016
• 出版时间：December 2016
• 年：2016
• 卷：88
• 期：6
• 页码：807-819
• 全文大小：1839K
• ISSN：1747-0285

文摘

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 4.7 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.