2. Academic Validation
  3. Rational Design of Covalent Kinase Inhibitors by an Integrated Computational Workflow (Kin-Cov)

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

  • J Med Chem. 2023 Jun 8;66(11):7405-7420. doi: 10.1021/acs.jmedchem.3c00088.
Yang Zhou 1,  Hang Yu 1,  Anna Constance Vind 2,  Lulu Kong 3,  Yiling Liu 1,  Xiaojuan Song 1,  Zhengchao Tu 1,  Caihong Yun 3,  Jeff B Smaill 4,  Qing-Wen Zhang 5,  Ke Ding 1,  Simon Bekker-Jensen 2,  Xiaoyun Lu 1
Affiliations

Affiliations

  • 1 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.
  • 2 Center for Healthy Aging, Department of Cellular and Molecular Medicine, University of Copenhagen, Blegdamsvej 3B, 2200 Copenhagen, Denmark.
  • 3 Department of Biochemistry and Biophysics, Institute of Systems Biomedicine and Beijing Key Laboratory of Tumor Systems Biology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing 100191, China.
  • 4 Auckland Cancer Society Research Centre, Faculty of Medical and Health Sciences and Maurice Wilkins Centre for Molecular Biodiscovery, The University of Auckland, Auckland 92019, New Zealand.
  • 5 State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao 999078, China.
PMID: 37220641 DOI: 10.1021/acs.jmedchem.3c00088
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 (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.

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