Rational Design of Covalent Kinase Inhibitors by an Integrated Computational Workflow (Kin-Cov)

摘要

Covalent kinase inhibitors (CKIs) hold great promisefor drug development.However, examples of computationally guided design of CKIs are stillscarce. Here, we present an integrated computational workflow (Kin-Cov)for rational design of CKIs. The design of the first covalent leucine-zipperand sterile-alpha motif kinase (ZAK) inhibitor was presented asan example to showcase the power of computational workflow for CKIdesign. The two representative compounds, 7 and 8, inhibited ZAK kinase with half-maximal inhibitory concentration(IC50) values of 9.1 and 11.5 nM, respectively. Compound 8 displayed an excellent ZAK target specificity in Kinomeprofiling against 378 wild-type kinases. Structural biology and cell-basedWestern blot washout assays validated the irreversible binding characteristicsof the compounds. Our study presents a rational approach for the designof CKIs based on the reactivity and accessibility of nucleophilicamino acid residues in a kinase. The workflow is generalizable andcan be applied to facilitate CKI-based drug design.