Institute of Biophysics and Department of Physics, Central China Normal University, Wuhan, 430079, China.
School of Physics and Engineering, Henan University of Science and Technology, Luoyang 471023, China.
Brief Bioinform. 2022 Jul 18;23(4). doi: 10.1093/bib/bbac290.
Cyclin-dependent kinase (Cdk) proteins play crucial roles in the cell cycle progression and are thus attractive drug targets for therapy against such aberrant cell cycle processes as cancer. Since most of the available Cdk inhibitors target the highly conserved catalytic ATP pocket and their lack of specificity often lead to side effects, it is imperative to identify and characterize less conserved non-catalytic pockets capable of interfering with the kinase activity allosterically. However, a systematic analysis of these allosteric druggable pockets is still in its infancy. Here, we summarize the existing Cdk pockets and their selectivity. Then, we outline a network-based pocket prediction approach (NetPocket) and illustrate its utility for systematically identifying the allosteric druggable pockets with case studies. Finally, we discuss potential future directions and their challenges.
细胞周期蛋白依赖性激酶（Cdk）蛋白在细胞周期进程中发挥着关键作用，因此是治疗癌症等异常细胞周期过程的有吸引力的药物靶点。由于大多数可用的 Cdk 抑制剂针对高度保守的催化 ATP 口袋，并且它们缺乏特异性往往会导致副作用，因此必须确定和表征能够变构干扰激酶活性的不太保守的非催化口袋。然而，对这些变构可药物口袋的系统分析仍处于起步阶段。在这里，我们总结了现有的 Cdk 口袋及其选择性。然后，我们概述了一种基于网络的口袋预测方法（NetPocket），并通过案例研究说明了其用于系统地识别变构可药物口袋的效用。最后，我们讨论了潜在的未来方向及其挑战。
