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Updated: Jul 11, 2025
Biosynthesis of a Flavonol from a Flavanone by Establishing a One-pot Bienzymatic Cascade
Published on: August 14, 2019
Natural flavonoids as promising 6-phosphogluconate dehydrogenase inhibitor candidates: In silico and in vitro
Şevki Adem1, Ümit Yırtıcı2, Mesut Aydın1
1Department of Chemistry, Faculty of Sciences, Çankırı Karatekin University, Çankırı, Turkey.
Abstract:
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 µM, while luteolin, kaempferol, apiin, galangin, and baicalin showed moderate effects with IC50 values between 54.15 and 138.91 µM. 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 µM, respectively. We calculated Ki values using the Cheng-Prusoff equation as between 0.44 and 14.88 µM. 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.
Insights
Plant-derived flavonoids show potent inhibitory effects against the 6-phosphogluconate dehydrogenase (6-PGD) enzyme. These compounds, particularly quercetin, demonstrate potential as novel anti-cancer drug candidates by targeting 6-PGD.
Area of Science:
- Biochemistry and Molecular Biology
- Pharmacology and Drug Discovery
- Phytochemistry
Background:
- Cancer treatment relies on identifying effective anti-cancer compounds.
- Plant-derived phytochemicals, especially flavonoids, are promising sources for novel therapeutics.
- The 6-phosphogluconate dehydrogenase (6-PGD) enzyme is a potential target in cancer therapy.
Purpose of the Study:
- To investigate the inhibitory effects of selected flavonoids on the 6-PGD enzyme.
- To elucidate the molecular mechanisms of flavonoid-enzyme interactions.
- To assess the potential of these flavonoids as anti-cancer drug leads.
Main Methods:
- In vitro enzyme inhibition assays to determine IC50 and Ki values.
- In silico molecular docking and molecular dynamic simulations to analyze binding interactions.
- Assessment of Absorption, Distribution, Metabolism, Excretion, and Toxicity (ADMET) properties.
- Network analysis to evaluate effects on cancer cell lines.
Main Results:
- Quercetin, myricetin, fisetin, morin, apigenin, and baicalein showed potent 6-PGD inhibition (IC50: 4.08–21.26 µM).
- Quercetin competitively inhibited 6-PGD with low Ki values, indicating strong binding affinity.
- Molecular modeling revealed hydrogen bonding interactions between flavonoid hydroxyl groups and the enzyme's active site.
- Simulations confirmed the stability of the 6-PGD-quercetin complex.
Conclusions:
- Flavonoids are potent inhibitors of 6-PGD, suggesting their therapeutic potential in cancer.
- The hydroxyl groups on the A and C rings of flavonoids are crucial for enzyme binding.
- Optimized flavonoids possess favorable drug-like properties and warrant further development as anti-cancer agents targeting 6-PGD.
