Discovery and validation of 2-styryl substituted benzoxazin-4-ones as a novel scaffold for rhomboid protease inhibitors
Language English Country Great Britain, England Media print-electronic
Document type Journal Article, Research Support, Non-U.S. Gov't
PubMed
29463448
DOI
10.1016/j.bmcl.2018.02.017
PII: S0960-894X(18)30106-9
Knihovny.cz E-resources
- Keywords
- Benzoxazinones, Inhibition, Intramembrane proteases, Molecular docking, Rhomboid proteases,
- MeSH
- Benzoxazines chemical synthesis chemistry MeSH
- Chymotrypsin chemistry MeSH
- DNA-Binding Proteins antagonists & inhibitors chemistry genetics MeSH
- Drosophila chemistry MeSH
- Endopeptidases chemistry genetics MeSH
- Enzyme Assays MeSH
- Escherichia coli enzymology MeSH
- Serine Proteinase Inhibitors chemical synthesis chemistry MeSH
- Catalytic Domain MeSH
- Humans MeSH
- Membrane Proteins antagonists & inhibitors chemistry genetics MeSH
- Mutation MeSH
- Drug Discovery MeSH
- Drosophila Proteins metabolism MeSH
- Escherichia coli Proteins antagonists & inhibitors chemistry genetics MeSH
- Serine chemistry MeSH
- Molecular Docking Simulation MeSH
- Cattle MeSH
- Styrenes chemical synthesis chemistry MeSH
- Transforming Growth Factor alpha metabolism MeSH
- Animals MeSH
- Check Tag
- Humans MeSH
- Cattle MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Names of Substances
- alpha-chymotrypsin MeSH Browser
- Benzoxazines MeSH
- Chymotrypsin MeSH
- DNA-Binding Proteins MeSH
- Endopeptidases MeSH
- GlpG protein, E coli MeSH Browser
- grk protein, Drosophila MeSH Browser
- Serine Proteinase Inhibitors MeSH
- Membrane Proteins MeSH
- Drosophila Proteins MeSH
- Escherichia coli Proteins MeSH
- Serine MeSH
- Styrenes MeSH
- Transforming Growth Factor alpha MeSH
Rhomboids are intramembrane serine proteases with diverse physiological functions in organisms ranging from archaea to humans. Crystal structure analysis has provided a detailed understanding of the catalytic mechanism, and rhomboids have been implicated in various disease contexts. Unfortunately, the design of specific rhomboid inhibitors has lagged behind, and previously described small molecule inhibitors displayed insufficient potency and/or selectivity. Using a computer-aided approach, we focused on the discovery of novel scaffolds with reduced liabilities and the possibility for broad structural variations. Docking studies with the E. coli rhomboid GlpG indicated that 2-styryl substituted benzoxazinones might comprise novel rhomboid inhibitors. Protease in vitro assays confirmed activity of 2-styryl substituted benzoxazinones against GlpG but not against the soluble serine protease α-chymotrypsin. Furthermore, mass spectrometry analysis demonstrated covalent modification of the catalytic residue Ser201, corroborating the predicted mechanism of inhibition and the formation of an acyl enzyme intermediate. In conclusion, 2-styryl substituted benzoxazinones are a novel rhomboid inhibitor scaffold with ample opportunity for optimization.
References provided by Crossref.org
4-Oxo-β-lactams as Covalent Inhibitors of the Mitochondrial Intramembrane Protease PARL
