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

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Standard

Rational Design of Covalent Kinase Inhibitors by an Integrated Computational Workflow (Kin-Cov). / Zhou, Yang; Yu, Hang; Vind, Anna Constance; Kong, Lulu; Liu, Yiling; Song, Xiaojuan; Tu, Zhengchao; Yun, Caihong; Smaill, Jeff B.; Zhang, Qing Wen; Ding, Ke; Bekker-Jensen, Simon; Lu, Xiaoyun.

I: Journal of Medicinal Chemistry, Bind 66, Nr. 11, 2023, s. 7405–7420.

Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt

Harvard

Zhou, Y, Yu, H, Vind, AC, Kong, L, Liu, Y, Song, X, Tu, Z, Yun, C, Smaill, JB, Zhang, QW, Ding, K, Bekker-Jensen, S & Lu, X 2023, 'Rational Design of Covalent Kinase Inhibitors by an Integrated Computational Workflow (Kin-Cov)', Journal of Medicinal Chemistry, bind 66, nr. 11, s. 7405–7420. https://doi.org/10.1021/acs.jmedchem.3c00088

APA

Zhou, Y., Yu, H., Vind, A. C., Kong, L., Liu, Y., Song, X., Tu, Z., Yun, C., Smaill, J. B., Zhang, Q. W., Ding, K., Bekker-Jensen, S., & Lu, X. (2023). Rational Design of Covalent Kinase Inhibitors by an Integrated Computational Workflow (Kin-Cov). Journal of Medicinal Chemistry, 66(11), 7405–7420. https://doi.org/10.1021/acs.jmedchem.3c00088

Vancouver

Zhou Y, Yu H, Vind AC, Kong L, Liu Y, Song X o.a. Rational Design of Covalent Kinase Inhibitors by an Integrated Computational Workflow (Kin-Cov). Journal of Medicinal Chemistry. 2023;66(11):7405–7420. https://doi.org/10.1021/acs.jmedchem.3c00088

Author

Zhou, Yang ; Yu, Hang ; Vind, Anna Constance ; Kong, Lulu ; Liu, Yiling ; Song, Xiaojuan ; Tu, Zhengchao ; Yun, Caihong ; Smaill, Jeff B. ; Zhang, Qing Wen ; Ding, Ke ; Bekker-Jensen, Simon ; Lu, Xiaoyun. / Rational Design of Covalent Kinase Inhibitors by an Integrated Computational Workflow (Kin-Cov). I: Journal of Medicinal Chemistry. 2023 ; Bind 66, Nr. 11. s. 7405–7420.

Bibtex

@article{ea0af5e1b34046f6be39ad8a4916b449,
title = "Rational Design of Covalent Kinase Inhibitors by an Integrated Computational Workflow (Kin-Cov)",
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.",
author = "Yang Zhou and Hang Yu and Vind, {Anna Constance} and Lulu Kong and Yiling Liu and Xiaojuan Song and Zhengchao Tu and Caihong Yun and Smaill, {Jeff B.} and Zhang, {Qing Wen} and Ke Ding and Simon Bekker-Jensen and Xiaoyun Lu",
note = "Publisher Copyright: {\textcopyright} 2023 American Chemical Society.",
year = "2023",
doi = "10.1021/acs.jmedchem.3c00088",
language = "English",
volume = "66",
pages = "7405–7420",
journal = "Journal of Medicinal Chemistry",
issn = "0022-2623",
publisher = "American Chemical Society",
number = "11",

}

RIS

TY - JOUR

T1 - Rational Design of Covalent Kinase Inhibitors by an Integrated Computational Workflow (Kin-Cov)

AU - Zhou, Yang

AU - Yu, Hang

AU - Vind, Anna Constance

AU - Kong, Lulu

AU - Liu, Yiling

AU - Song, Xiaojuan

AU - Tu, Zhengchao

AU - Yun, Caihong

AU - Smaill, Jeff B.

AU - Zhang, Qing Wen

AU - Ding, Ke

AU - Bekker-Jensen, Simon

AU - Lu, Xiaoyun

N1 - Publisher Copyright: © 2023 American Chemical Society.

PY - 2023

Y1 - 2023

N2 - 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.

AB - 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.

U2 - 10.1021/acs.jmedchem.3c00088

DO - 10.1021/acs.jmedchem.3c00088

M3 - Journal article

C2 - 37220641

AN - SCOPUS:85162207657

VL - 66

SP - 7405

EP - 7420

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

SN - 0022-2623

IS - 11

ER -

ID: 358559974