TWIK-related acid-sensitive potassium channel 1 (TASK-1) is expressed ubiquitously across various tissues and plays a significant role in neural activity and anesthetic modulation, making it a crucial target for pharmaceutical research. The high conservation of binding site residues within the TASK family, particularly between TASK-1 and TASK-3, necessitates the development of selective inhibitors for TASK-1. In this study, we utilized a combination of structure-based drug design (SBDD) and ligand-based drug design (LBDD) approaches. Initially, several bisamide-centered molecules were designed using the program MolAICal, which is recognized for its ability to generate selective inhibitors containing bisamide segments, and conducted preliminary screening via molecular docking. Subsequently, 3D-QSAR models were developed for 56 bisamide derivatives targeting TASK-1 and TASK-3, with the models exhibiting robust predictive capabilities (TASK-1: Q² = 0.61, R²_pred = 0.84; TASK-3: Q² = 0.60, R²_pred = 0.71). Using these models, the candidate molecules were subjected to activity prediction and subsequent filtering. Ultimately, molecular dynamics simulations, coupled with free energy calculations, pinpointed two bisamide-core molecules with favorable ADMET properties as potential selective inhibitors for TASK-1. Furthermore, molecular dynamics simulations revealed the critical role of the key residue Leu122 in conferring selectivity to bisamide compounds for TASK-1 channel proteins.

中文翻译：

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TASK-1 钾通道双酰胺抑制剂的计算机设计


TWIK 相关酸敏感钾通道 1 （TASK-1） 在各种组织中普遍表达，并在神经活动和麻醉剂调节中发挥重要作用，使其成为药物研究的关键靶标。TASK 家族中结合位点残基的高度保守性，尤其是在 TASK-1 和 TASK-3 之间，因此需要开发 TASK-1 的选择性抑制剂。在这项研究中，我们结合了基于结构的药物设计 （SBDD） 和基于配体的药物设计 （LBDD） 方法。最初，使用 MolAICal 程序设计了几种以比酰胺为中心的分子，该程序以其生成含有双酰胺片段的选择性抑制剂的能力而得到认可，并通过分子对接进行了初步筛选。随后，为靶向 TASK-1 和 TASK-3 的 56 种双酰胺衍生物开发了 3D-QSAR 模型，这些模型表现出强大的预测能力 （TASK-1：Q² = 0.61，R ²_pred = 0.84;任务 3：Q² = 0.60，R ²_pred = 0.71）。使用这些模型，对候选分子进行活性预测和随后的过滤。最终，分子动力学模拟与自由能计算相结合，确定了两个具有良好 ADMET 特性的双酰胺核心分子作为 TASK-1 的潜在选择性抑制剂。此外，分子动力学模拟揭示了关键残基 Leu122 在赋予 TASK-1 通道蛋白双酰胺化合物选择性方面的关键作用。