Natural flavonoids as promising 6-phosphogluconate dehydrogenase inhibitor candidates: In silico and in vitro assessments
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Tarih
2024
Dergi Başlığı
Dergi ISSN
Cilt Başlığı
Yayıncı
Wiley-V C H Verlag Gmbh
Erişim Hakkı
info:eu-repo/semantics/openAccess
Özet
The primary strategy in the fight against cancer is to screen compounds that may be effective on different types of cancer. Compounds from plants seem to be a good source. The present study investigated the inhibitory effects of some flavonoids on the 6-phosphogluconate dehydrogenase (6-PGD) enzyme. We determined that quercetin, myricetin, fisetin, morin, apigenin, and baicalein exhibited powerful inhibition effects with IC50 values between 4.08 and 21.26 mu M, while luteolin, kaempferol, apiin, galangin, and baicalin showed moderate effects with IC50 values between 54.15 and 138.91 mu M. Quercetin competitively inhibited the binding of NADP and 6-phosphogluconate to the 6-PGD enzyme with Ki values of 0.527 +/- 0.251 and 0.374 +/- 0.138 mu M, respectively. We calculated Ki values using the Cheng-Prusoff equation as between 0.44 and 14.88 mu M. The possible interaction details of polyphenols with the active site of 6-PGD were analyzed with docking software. In silico and in vitro studies indicated that the -OH groups on the A and C ring of flavonoids bind to the enzyme's active site via hydrogen bonding, while the -OH groups on the C ring contributed significantly to the increase in the inhibitory potentials of the molecules. Molecular dynamic simulations tested the stability of the 6-PGD-quercetin complex during 100 ns. These phytochemicals were suitable for drug use when optimized with absorption, distribution, metabolism, excretion, and toxicity (ADMET) criteria. The effects of the studied compounds on cancer cell lines of potential targets were demonstrated by network analysis. In conclusion, this study suggests that flavonoids found to be potent inhibitors could serve as leading candidates to treat many cancers via 6-PGD inhibition. Quercetin, myricetin, fisetin, morin, apigenin, and baicalein are shown to exhibit powerful inhibition effects with IC50 values between 4.08 and 21.26 mu M. The interaction details with the active site of 6-phosphogluconate dehydrogenase were analyzed by molecular docking and molecular dynamics simulation software. These phytochemicals were generally suitable for drug use when optimized according to absorption, distribution, metabolism, excretion, and toxicity (ADMET) criteria.image
Açıklama
Anahtar Kelimeler
6-phosphogluconate dehydrogenase; ADMET; cancer; flavonoid; molecular docking and dynamics
Kaynak
Archiv Der Pharmazie
WoS Q Değeri
Q1
Scopus Q Değeri
Q1
Cilt
357
Sayı
1
