Rational Design, Synthesis, and Computational Investigation of Dihydropyridine [2,3-d] Pyrimidines as Polyphenol Oxidase Inhibitors with Improved Potency

Basit Öğe Kaydı
dc.authorscopusid55342808300en_US
dc.authorscopusid57203286944en_US
dc.authorscopusid37099630300en_US
dc.authorscopusid58110944900en_US
dc.authorscopusid57191499641en_US
dc.authorscopusid57224659920en_US
dc.authorscopusid57203542863en_US
dc.contributor.authorKaya, Mustafa Oguzhan
dc.contributor.authorKerimak-Oner, Mine Nazan
dc.contributor.authorDemirci, Tuna
dc.contributor.authorMusatat, Ahmad Badreddin
dc.contributor.authorOzdemir, Oguzhan
dc.contributor.authorKaya, Yesim
dc.contributor.authorArslan, Mustafa
dc.date.accessioned2024-08-23T16:07:07Z
dc.date.available2024-08-23T16:07:07Z
dc.date.issued2024en_US
dc.departmentDüzce Üniversitesien_US
dc.description.abstractPolyphenol oxidase (PPO) is an industrially important enzyme associated with browning reactions. In the present study, a set of ten new dihydropyridine [2,3-d] pyrimidines (TD-Hid-1-10) were synthesized and was found to be proven characteristically by 1H NMR, 13C NMR, IR, elemental analysis, and assessed as possible PPO inhibitors. PPO was purified from banana using three-phase partitioning, achieving an 18.65-fold purification and 136.47% activity recovery. Enzyme kinetics revealed that the compounds TD-Hid-6 and TD-Hid-7 are to be the most potent inhibitors, exhibiting mixed-type inhibition profile with IC50 values of 1.14 mu M, 5.29 mu M respectively against purified PPO enzyme. Electronic structure calculations at the B3LYP/PBE0 level of theories using def-2 SVP, def2-TZVP basis sets with various molecular descriptors characterized the electronic behavior of studied derivatives TD-Hid-1-10. Molecular electrostatic potential (MEP) and reduced density gradient analyses of RDG-NCI provided insights into charge distributions and weak intermolecular interactions. Docking study simulations predicted binding poses within crucial amino acid sequence in the 2y9x enzyme's active site, which is typically similar in sequence to the PPO form is not allowed. Ligands were analysed in terms of binding energies, inhibitor concentrations (mM) and various molecular interactions such as H-bonds, H-carbon, pi-carbon, pi-sigma, pi-sigma, pi-pi T-shaped, pi-pi stacked, pi-alkyl, Van der Waals and Cu interactions. The lowest binding energy (-7.83 kcal/mol) and the highest inhibitory effect (1.83 mM) were shown by the ligand Td-Hid-6, which forms H-bonds with Met280 and Asn260, exhibits pi-sigma interactions with His61 and pi-alkyl interactions with Val283. Other ligands also showed different interactions with various amino acids; for example, the Td-Hid-1 ligand formed H-bonds with His244 and showed pi-sigma interactions with His244 and Val283.en_US
dc.description.sponsorshipSakarya University [2012-02-04-033/2016-50-02-002]en_US
dc.description.sponsorshipThis work was supported by the Research Fund of Sakarya University (2012-02-04-033/2016-50-02-002) and authors are thankful to Duezce University Scientific and Technological Research Laboratory for providing spectral data. DAS:No datasets were generated or analysed during the current study.en_US
dc.identifier.doi10.1007/s10930-024-10220-1
dc.identifier.issn1572-3887
dc.identifier.issn1875-8355
dc.identifier.pmid39097848en_US
dc.identifier.scopus2-s2.0-85200388429en_US
dc.identifier.scopusqualityQ1en_US
dc.identifier.urihttps://doi.org/10.1007/s10930-024-10220-1
dc.identifier.urihttps://hdl.handle.net/20.500.12684/14506
dc.identifier.wosWOS:001283264400001en_US
dc.identifier.wosqualityN/Aen_US
dc.indekslendigikaynakWeb of Scienceen_US
dc.indekslendigikaynakScopusen_US
dc.indekslendigikaynakPubMeden_US
dc.language.isoenen_US
dc.publisherSpringeren_US
dc.relation.ispartofProtein Journalen_US
dc.relation.publicationcategoryMakale - Uluslararası Hakemli Dergi - Kurum Öğretim Elemanıen_US
dc.rightsinfo:eu-repo/semantics/closedAccessen_US
dc.subject1,4-Dihydropyridineen_US
dc.subjectPolyphenol Oxidaseen_US
dc.subjectMolecular Electronic Potentialen_US
dc.subjectDFTen_US
dc.subjectMolecular Dockingen_US
dc.subjectDrug Discoveryen_US
dc.subjectPurificationen_US
dc.subjectElectronen_US
dc.subjectSolubilityen_US
dc.subjectAbsorptionen_US
dc.subjectExtractionen_US
dc.subjectEnergiesen_US
dc.subjectAgentsen_US
dc.subjectL.en_US
dc.titleRational Design, Synthesis, and Computational Investigation of Dihydropyridine [2,3-d] Pyrimidines as Polyphenol Oxidase Inhibitors with Improved Potencyen_US
dc.typeArticleen_US

Dosyalar

Koleksiyon

WoS İndeksli Yayınlar Koleksiyonu
PubMed İndeksli Yayınlar Koleksiyonu
Scopus İndeksli Yayınlar Koleksiyonu