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J Med Chem. 2017 Apr 13;60(7):2879-2889. doi: 10.1021/acs.jmedchem.6b01815. Epub 2017 Apr 4.

Determining Cysteines Available for Covalent Inhibition Across the Human Kinome.

Author information

1
National Center for Biotechnology Information, National Library of Medicine, National Institutes of Health , Bethesda, Maryland 20892, United States.
2
High Magnetic Field Laboratory, Chinese Academy of Sciences , Hefei, Anhui 230031, China.
3
Laboratory of Biomolecular Research, Paul Scherrer Institute , 5232 Villigen, Switzerland.
4
Department of Computer Science, Hunter College, The City University of New York , New York, New York 10065, United States.
5
The Graduate Center, The City University of New York , New York, New York 10016, United States.
6
Office of the Director, National Institutes of Health , Bethesda, Maryland 20892, United States.

Abstract

Covalently bound protein kinase inhibitors have been frequently designed to target noncatalytic cysteines at the ATP binding site. Thus, it is important to know if a given cysteine can form a covalent bond. Here we combine a function-site interaction fingerprint method and DFT calculations to determine the potential of cysteines to form a covalent interaction with an inhibitor. By harnessing the human structural kinome, a comprehensive structure-based binding site cysteine data set was assembled. The orientation of the cysteine thiol group indicates which cysteines can potentially form covalent bonds. These covalent inhibitor easy-available cysteines are located within five regions: P-loop, roof of pocket, front pocket, catalytic-2 of the catalytic loop, and DFG-3 close to the DFG peptide. In an independent test set these cysteines covered 95% of covalent kinase inhibitors. This study provides new insights into cysteine reactivity and preference which is important for the prospective development of covalent kinase inhibitors.

PMID:
28326775
PMCID:
PMC5493210
DOI:
10.1021/acs.jmedchem.6b01815
[Indexed for MEDLINE]
Free PMC Article

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