Covalent inhibitors: an opportunity for rational target selectivity
| Autor: | Roman Lagoutte, Nicolas Winssinger, Remi Patouret |
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| Rok vydání: | 2017 |
| Předmět: |
Biological Products
010405 organic chemistry Chemistry 010402 general chemistry 01 natural sciences Biochemistry Combinatorial chemistry 0104 chemical sciences Analytical Chemistry Residue (chemistry) Protein structure Nucleophile Covalent bond Proteome Electrophile ddc:540 Drug Discovery Animals Humans Amino Acid Sequence Enzyme Inhibitors Selectivity Cysteine |
| Zdroj: | Current Opinion in Chemical Biology, Vol. 39 (2017) pp. 54-63 |
| ISSN: | 1879-0402 1367-5931 |
| Popis: | There is a resurging interest in compounds that engage their target through covalent interactions. Cysteine’s thiol is endowed with enhanced reactivity, making it the nucleophile of choice for covalent engagement with a ligand aligning an electrophilic trap with a cysteine residue in a target of interest. The paucity of cysteine in the proteome coupled to the fact that closely related proteins do not necessarily share a given cysteine residue enable a level of unprecedented rational target selectivity. The recent demonstration that a lysine’s amine can also be engaged covalently with a mild electrophile extends the potential of covalent inhibitors. The growing database of protein structures facilitates the discovery of covalent inhibitors while the advent of proteomic technologies enables a finer resolution in the selectivity of covalently engaged proteins. Here, we discuss recent examples of discovery and design of covalent inhibitors. |
| Databáze: | OpenAIRE |
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