期刊
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
卷 56, 期 48, 页码 15200-15209出版社
WILEY-V C H VERLAG GMBH
DOI: 10.1002/anie.201707630
关键词
drug design; inhibitors; lysine; medicinal chemistry; structural biology
资金
- ICR Chairman's Studentship Award
- Cancer Research UK [C309/A8274, C309/A11566]
- Cancer Research UK [11566] Funding Source: researchfish
Targeted covalent inhibitors have gained widespread attention in drug discovery as a validated method to circumvent acquired resistance in oncology. This strategy exploits small-molecule/protein crystal structures to design tightly binding ligands with appropriately positioned electrophilic warheads. Whilst most focus has been on targeting binding-site cysteine residues, targeting nucleophilic lysine residues can also represent a viable approach to irreversible inhibition. However, owing to the basicity of the E-amino group in lysine, this strategy generates a number of specific challenges. Herein, we review the key principles for inhibitor design, give historical examples, and present recent developments that demonstrate the potential of lysine targeting for future drug discovery.
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