Rational Design of Covalent Kinase Inhibitors by an Integrated Computational Workflow (Kin-Cov)
Research output: Contribution to journal › Journal article › Research › peer-review
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 (IC50) 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.
Original language | English |
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Journal | Journal of Medicinal Chemistry |
Volume | 66 |
Issue number | 11 |
Pages (from-to) | 7405–7420 |
ISSN | 0022-2623 |
DOIs | |
Publication status | Published - 2023 |
Bibliographical note
Publisher Copyright:
© 2023 American Chemical Society.
ID: 358559974