Shanghai Key Laboratory of Regulatory Biology, School of Life Sciences, East China Normal University, Shanghai 200241, China.
Suzhou Institute of Drug Innovation, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Suzhou, Jiangsu 215123, China.
J Med Chem. 2022 Aug 11;65(15):10285-10299. doi: 10.1021/acs.jmedchem.1c02115. Epub 2022 Jul 25.
Under the known pharmacological activation mechanisms, activators allosterically or directly open potassium channel gates. However, herein, molecular dynamics simulations on TREK-1, a member of the channel class gated at the filter, suggested that negatively charged activators act with a gate-independent mechanism where compounds increase currents by promoting ions passing through the central cavity. Then, based on studies of KCNQ2, we uncovered that this noncanonical activation mechanism is shared by the other channel class gated at the helix-bundle crossing. Rational drug design found a novel KCNQ2 agonist, CLE030, which stably binds to the central cavity. Functional analysis, molecular dynamics simulations, and calculations of the potential of mean force revealed that the carbonyl oxygen of CLE030 influences permeant ions in the central cavity to contribute to its activation effects. Together, this study discovered a ligand-to-ion activation mechanism for channels that bypasses their gates and thus is conserved across subfamilies with different gates.
在已知的药理学激活机制下，激活剂通过变构或直接打开钾通道门。然而，本文通过对通道门在滤波器处打开的 TREK-1 成员的分子动力学模拟表明，带负电荷的激活剂通过一种不依赖门的机制起作用，化合物通过促进离子通过中央腔来增加电流。然后，基于对 KCNQ2 的研究，我们发现这种非典型激活机制在其他在螺旋束交叉处打开的通道类别中是共享的。合理的药物设计发现了一种新型的 KCNQ2 激动剂 CLE030，它可以稳定地结合到中央腔。功能分析、分子动力学模拟和平均力势的计算表明，CLE030 的羰基氧影响中央腔内的可渗透离子，从而有助于其激活作用。总的来说，这项研究发现了一种绕过通道门的配体到离子激活机制，这种机制在具有不同门的亚家族中是保守的。
