Structural Specificity of Flavonoids in the Inhibition of Human Fructose 1,6-Bisphosphatase

• Type: Article in International Scientific Journal
• Date: 2020

Authors

Proenca, C (Author) Other; Oliveira, A (Author) Other; Freitas, M (Author) Other; Ribeiro, D (Author) Other; Sousa, JLC (Author) Other; Ramos, MJ (Author) FCUP; Silva, AMS (Author) Other; Pedro A Fernandes (Author) FCUP; Eduarda Fernandes (Author) FFUP

Journal

Title: Journal of Natural Products

Vol. 83

Pages: 1541-1552

ISSN: 0163-3864

Publisher: American Chemical Society

Indexing

ISI Web of Knowledge - 14 Citations

Scopus - 15 Citations

Other information

Authenticus ID: P-00S-4Z2

DOI: 10.1021/acs.jnatprod.0c00014

Abstract (EN): 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.

Language: English

Type (Professor's evaluation): Scientific

No. of pages: 12