International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Discovery of Chinese Ministry of Education (MOE), Guangzhou City Key Laboratory of Precision Chemical Drug Development, School of Pharmacy, Jinan University, 855 Xingye Avenue, Guangzhou 510632, China.
Center for Healthy Aging, Department of Cellular and Molecular Medicine, University of Copenhagen, Blegdamsvej 3B, 2200 Copenhagen, Denmark.
J Med Chem. 2023 Jun 8;66(11):7405-7420. doi: 10.1021/acs.jmedchem.3c00088. Epub 2023 May 23.
Covalent kinase inhibitors (CKIs) hold great promise for drug development. However, examples of computationally guided design of CKIs are still scarce. Here, we present an integrated computational workflow (Kin-Cov) for rational design of CKIs. The design of the first covalent leucine-zipper and sterile-α motif kinase (ZAK) inhibitor was presented as an example to showcase the power of computational workflow for CKI design. The two representative compounds, and , inhibited ZAK kinase with half-maximal inhibitory concentration (IC) values of 9.1 and 11.5 nM, respectively. Compound displayed an excellent ZAK target specificity in Kinome profiling against 378 wild-type kinases. Structural biology and cell-based Western blot washout assays validated the irreversible binding characteristics of the compounds. Our study presents a rational approach for the design of CKIs based on the reactivity and accessibility of nucleophilic amino acid residues in a kinase. The workflow is generalizable and can be applied to facilitate CKI-based drug design.
共价激酶抑制剂 (CKIs) 在药物开发中具有广阔的前景。然而，基于计算指导的 CKIs 设计实例仍然很少。在这里，我们提出了一种集成的计算工作流程 (Kin-Cov)，用于合理设计 CKIs。我们以设计首个共价亮氨酸拉链和无菌-α基序激酶 (ZAK) 抑制剂为例，展示了计算工作流程在 CKI 设计中的强大功能。这两种代表性化合物 和 对 ZAK 激酶的抑制作用，半数最大抑制浓度 (IC) 值分别为 9.1 和 11.5 nM。化合物 在针对 378 种野生型激酶的激酶组谱分析中表现出优异的 ZAK 靶标特异性。结构生物学和基于细胞的 Western blot 洗脱测定验证了化合物的不可逆结合特性。我们的研究提出了一种基于激酶中亲核氨基酸残基的反应性和可及性设计 CKIs 的合理方法。该工作流程具有通用性，可应用于促进基于 CKI 的药物设计。
