Determining Cysteines Available for Covalent Inhibition Across the Human Kinome.
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.
National Center for Biotechnology Information, National Library of Medicine, National Institutes of Health , Bethesda, Maryland 20892, United States.
Zheng
0000-0003-1453-3230
Z
Zhao
High Magnetic Field Laboratory, Chinese Academy of Sciences , Hefei, Anhui 230031, China.
Qingsong
0000-0002-7829-2547
Q
Liu
National Center for Biotechnology Information, National Library of Medicine, National Institutes of Health , Bethesda, Maryland 20892, United States.|Laboratory of Biomolecular Research, Paul Scherrer Institute , 5232 Villigen, Switzerland.
Spencer
S
Bliven
Department of Computer Science, Hunter College, The City University of New York , New York, New York 10065, United States.|The Graduate Center, The City University of New York , New York, New York 10016, United States.
Lei
L
Xie
National Center for Biotechnology Information, National Library of Medicine, National Institutes of Health , Bethesda, Maryland 20892, United States.|Office of the Director, National Institutes of Health , Bethesda, Maryland 20892, United States.
Philip E
PE
Bourne
D001665:Binding Sites; D003545:Cysteine / Q000032:analysis / Q000378:metabolism*; D006801:Humans; D011487:Protein Conformation / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D011494:Protein Kinases / Q000737:chemistry / Q000378:metabolism*; D013329:Structure-Activity Relationship
D047428:Protein Kinase Inhibitors; D011494:Protein Kinases; D003545:Cysteine