Natural flavonoids as promising lactate dehydrogenase A inhibitors: Comprehensive in vitro and in silico analysis

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dc.authoridYirtici, Umit/0000-0002-0142-6105
dc.contributor.authorYirtici, Umit
dc.date.accessioned2025-01-21T16:42:48Z
dc.date.available2025-01-21T16:42:48Z
dc.date.issued2024
dc.departmentKırıkkale Üniversitesi
dc.description.abstractThe inhibitory potential of 17 flavonoids on lactate dehydrogenase A (LDHA), a key enzyme in the downstream process of aerobic glycolysis in cancer cells, is investigated. Fisetin exhibited excellent inhibitory activity (IC50 = 0.066 mu M). Quercetin 3-beta-D-glucoside, quercetin 3-galactoside, luteolin, neoeriocitrin, and luteolin 7-O-beta-D-glucoside showed good inhibitory activity (IC50 = 1.397-15.730 mu M). Biochanin A, baicalein, quercetin, scutellarein-7-glucuronide, diosmetin, baicalein 7-O-beta-D-glucuronide, and apigenin 7-apioglucoside demonstrated moderate inhibitory activity (IC50 = 33.007-86.643 mu M). Eriodictyol, quercetin 7-O-beta-D-glucoside, apigenin 7-O-beta-D-glucoside, and epicatechin were inactive. The Lineweaver-Burk plot showed that fisetin competitively inhibits NADH binding (Ki = 0.024 mu M). Ki values for other compounds were calculated using the Cheng-Prusoff equation (Ki = 0.2799-2.1661 mu M). The study revealed that the inhibitory effect of flavonoids varies with the number and position of OH groups and bound sugars. Molecular docking analyses indicated that flavonoids exhibited strong interactions with the NADH binding site of LDHA through hydrophobic interactions and hydrogen bonds. Molecular dynamic simulations tested the stability of the fisetin-LDHA complex over 100 ns and showed fisetin's high binding affinity to LDHA, maintaining strong hydrogen bonds. The binding energy of fisetin with LDHA was -33.928 kcal/mol, indicating its effectiveness as an LDHA inhibitor. Consequently, flavonoids identified as strong inhibitors could be potential cancer treatment sources through LDHA inhibition. Fisetin, quercetin 3-beta-D-glucoside, quercetin 3-galactoside, and luteolin are shown to exhibit powerful inhibition effects, with IC50 values between 0.066 and 1.792 mu M. The details of possible interactions with the active site of lactate dehydrogenase A were analyzed by molecular docking and molecular dynamics simulation. image
dc.description.sponsorshipAll experimental studies were carried out at Krkkale University Scientific and Technological Researches Application and Research Centre Directorate (KuBTUAM).
dc.identifier.doi10.1002/ardp.202400455
dc.identifier.issn0365-6233
dc.identifier.issn1521-4184
dc.identifier.issue9
dc.identifier.pmid39054614
dc.identifier.scopus2-s2.0-85199909321
dc.identifier.scopusqualityQ1
dc.identifier.urihttps://doi.org/10.1002/ardp.202400455
dc.identifier.urihttps://hdl.handle.net/20.500.12587/25141
dc.identifier.volume357
dc.identifier.wosWOS:001275912100001
dc.identifier.wosqualityN/A
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.subjectenzyme inhibition; flavonoids; lactate dehydrogenase A; molecular docking; molecular dynamics
dc.titleNatural flavonoids as promising lactate dehydrogenase A inhibitors: Comprehensive in vitro and in silico analysis
dc.typeArticle

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