Natural flavonoids as promising 6-phosphogluconate dehydrogenase inhibitor candidates: In silico and in vitro assessments

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dc.authoridAdem, Sevki/0000-0003-2146-5870
dc.authoridYirtici, Umit/0000-0002-0142-6105
dc.authoridRawat, Ravi/0000-0001-6510-1046
dc.contributor.authorAdem, Sevki
dc.contributor.authorYirtici, Umit
dc.contributor.authorAydin, Mesut
dc.contributor.authorRawat, Ravi
dc.contributor.authorEyupoglu, Volkan
dc.date.accessioned2025-01-21T16:42:48Z
dc.date.available2025-01-21T16:42:48Z
dc.date.issued2024
dc.departmentKırıkkale Üniversitesi
dc.description.abstractThe 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
dc.description.sponsorshipCankimath;rimath; Karatekin University [FF111115L34]
dc.description.sponsorshipCank & imath;r & imath; Karatekin University supported this study with project number FF111115L34.
dc.identifier.doi10.1002/ardp.202300326
dc.identifier.issn0365-6233
dc.identifier.issn1521-4184
dc.identifier.issue1
dc.identifier.pmid37933686
dc.identifier.scopus2-s2.0-85176152758
dc.identifier.scopusqualityQ1
dc.identifier.urihttps://doi.org/10.1002/ardp.202300326
dc.identifier.urihttps://hdl.handle.net/20.500.12587/25140
dc.identifier.volume357
dc.identifier.wosWOS:001097263200001
dc.identifier.wosqualityQ1
dc.indekslendigikaynakWeb of Science
dc.indekslendigikaynakScopus
dc.indekslendigikaynakPubMed
dc.language.isoen
dc.publisherWiley-V C H Verlag Gmbh
dc.relation.ispartofArchiv Der Pharmazie
dc.relation.publicationcategoryMakale - Uluslararası Hakemli Dergi - Kurum Öğretim Elemanı
dc.rightsinfo:eu-repo/semantics/openAccess
dc.snmzKA_20241229
dc.subject6-phosphogluconate dehydrogenase; ADMET; cancer; flavonoid; molecular docking and dynamics
dc.titleNatural flavonoids as promising 6-phosphogluconate dehydrogenase inhibitor candidates: In silico and in vitro assessments
dc.typeArticle

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