Počet záznamů: 1
Discovery and validation of 2-styryl substituted benzoxazin-4-ones as a novel scaffold for rhomboid protease inhibitors
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SYSNO ASEP 0490090 Druh ASEP J - Článek v odborném periodiku Zařazení RIV J - Článek v odborném periodiku Poddruh J Článek ve WOS Název Discovery and validation of 2-styryl substituted benzoxazin-4-ones as a novel scaffold for rhomboid protease inhibitors Tvůrce(i) Goel, P. (DE)
Jumpertz, T. (DE)
Tichá, Anežka (UOCHB-X) ORCID, RID
Ogorek, I. (DE)
Mikles, David C. (UOCHB-X)
Hubálek, Martin (UOCHB-X) RID, ORCID
Pietrzik, C. U. (DE)
Stříšovský, Kvido (UOCHB-X) RID, ORCID
Schmidt, B. (DE)
Weggen, S. (DE)Zdroj.dok. Bioorganic and Medicinal Chemistry Letters. - : Elsevier - ISSN 0960-894X
Roč. 28, č. 8 (2018), s. 1417-1422Poč.str. 6 s. Jazyk dok. eng - angličtina Země vyd. GB - Velká Británie Klíč. slova rhomboid proteases ; intramembrane proteases ; benzoxazinones ; molecular docking ; inhibition Vědní obor RIV CE - Biochemie Obor OECD Biochemistry and molecular biology CEP LK11206 GA MŠMT - Ministerstvo školství, mládeže a tělovýchovy LO1302 GA MŠMT - Ministerstvo školství, mládeže a tělovýchovy Institucionální podpora UOCHB-X - RVO:61388963 UT WOS 000429408300029 EID SCOPUS 85042086167 DOI 10.1016/j.bmcl.2018.02.017 Anotace 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 alpha-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. Pracoviště Ústav organické chemie a biochemie Kontakt asep@uochb.cas.cz ; Kateřina Šperková, Tel.: 232 002 584 ; Jana Procházková, Tel.: 220 183 418 Rok sběru 2019
Počet záznamů: 1