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Design of bisamide inhibitors of the TASK-1 potassium channel in silico

文献类型： 外文期刊

作者： Liu, Lu 1 ; Liu, Jixiang 1 ; Chen, Liang 2 ; Na, Risong 3 ; Yang, Lianjuan 4 ; Liu, Xiaoping 4 ; Zhao, Xi 1 ;

作者机构： 1.Jilin Univ, Inst Theoret Chem, Coll Chem, Changchun 130061, Peoples R China

2.Jilin Acad Agr Sci, Soybean Res Inst, Changchun 130033, Peoples R China

3.Henan Agr Univ, Collaborat Innovat Ctr Henan Grain Crops, Natl Key Lab Wheat & Maize Crop Sci, Coll Plant Protect, Zhengzhou 450002, Peoples R China

4.Tongji Univ, Shanghai Skin Dis Hosp, Dept Med Mycol, Sch Med, Shanghai 200443, Peoples R China

期刊名称：PHYSICAL CHEMISTRY CHEMICAL PHYSICS （ 影响因子：2.9； 五年影响因子：3.0 ）

ISSN： 1463-9076

年卷期： 2024 年 27 卷 1 期

页码：

收录情况： SCI

摘要： 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, R2pred = 0.84; TASK-3: Q2 = 0.60, R2pred = 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.

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