期刊
JOURNAL OF NATURAL PRODUCTS
卷 83, 期 5, 页码 1541-1552出版社
AMER CHEMICAL SOC
DOI: 10.1021/acs.jnatprod.0c00014
关键词
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资金
- FCT/MCTES through national funds [UIDB/50006/2020]
- Programa Operacional Competitividade e Internacionalizacao (COMPETE) [POCI-01-0145-FEDER-029241, UID/QUI/062/2019]
- FCT [SFRH/BD/116005/2016]
- Fundo Social Europeu (FSE)
- national funds of Ministerio da Ciencia, Tecnologia e Ensino Superior (MCTES)
- European Union [FEDER funds through the Operational Competitiveness Program (COMPETE)] [POCI-01-0145-FEDER-029253, POCI-01-0145-FEDER-029248]
- Fundação para a Ciência e a Tecnologia [SFRH/BD/116005/2016] Funding Source: FCT
Liver fructose 1,6-bisphosphatase (FBPase) is a recognized regulatory enzyme of the gluconeogenesis pathway, which has emerged as a valid target to control gluconeogenesis-mediated overproduction of glucose. As such, the management of diabetes with FBPase inhibitors represents a potential alternative for the currently used antidiabetic agents. In this study, the FBPase inhibition of a panel of 55 structurally related flavonoids was tested, through a microanalysis screening system. Then, a subset of seven active inhibitors and their close chemical relatives were further evaluated by molecular dynamics (MD) simulations using a linear interaction energy (LIE) approach. The results obtained showed that D14 (herbacetin) was the most potent inhibitor, suggesting that the presence of -OH groups at the C-3, C-4', C-5, C-7, and C-8 positions, as well as the double bond between C-2 and C-3 and the 4-oxo function at the pyrone ring, are favorable for the intended effect. Furthermore, D14 (herbacetin) is stabilized by a strong interaction with the Glu30 side chain and the Thr24 backbone of FBPase. This is the first investigation studying the in vitro inhibitory effect of a panel of flavonoids against human liver FBPase, thus representing a potentially important step for the search and design of novel inhibitors of this enzyme.
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