Rational Design of Covalent Kinase Inhibitors by an Integrated Computational Workflow (Kin-Cov)
Yang Zhou, Hang Yu, Anna Vind, Lulu Kong, Yiling Liu, Xiaojuan Song, Zhengchao Tu, Cai‐Hong Yun, Jeff B. Smaill, Qingwen Zhang, Ke Ding, Simon Bekker‐Jensen, Xiaoyun Lu
Abstract
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, 7 and 8, inhibited ZAK kinase with half-maximal inhibitory concentration (IC 50 ) values of 9.1 and 11.5 nM, respectively. Compound 8 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.