Determining Cysteines Available for Covalent Inhibition Across the Human Kinome
| Autor: | Zheng Zhao, Lei Xie, Philip E. Bourne, Spencer Bliven, Qingsong Liu |
|---|---|
| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Binding Sites Protein Conformation Stereochemistry Covalent Interaction Article Structure-Activity Relationship 03 medical and health sciences chemistry.chemical_compound 030104 developmental biology chemistry Covalent bond Drug Discovery Humans Molecular Medicine Structure–activity relationship Kinome Cysteine Binding site Protein kinase A Protein Kinase Inhibitors Protein Kinases Cysteine metabolism |
| Zdroj: | Journal of Medicinal Chemistry. 60:2879-2889 |
| ISSN: | 1520-4804 0022-2623 |
| DOI: | 10.1021/acs.jmedchem.6b01815 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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