Koksal, MuratŞekerler, TurgutŞener, Azize2025-08-102025-08-1020252630-634410.12991/jrespharm.16262212-s2.0-105012428466https://doi.org/10.12991/jrespharm.1626221https://search.trdizin.gov.tr/en/yayin/detay/1340335/the-effect-of-vitamin-d-and-paricalcitol-on-protein-disulfide-isomeraseProtein disulfide isomerase (PDI), a multifunctional protein plays an important role as oxidoreductase, isomerase and chaperone in the cell. Prior studies have identified PDI is highly expressed in many different cancer types and presented as a new potential target for cancer treatment. Here, we investigated vitamin D and its analogue paricalcitol in silico interaction of the human PDI and inhibition of PDI reductase activity in vitro. We observed a non-covalent mechanism where the main skeleton of the vitamin D3 ans paricalcitol sturcture is located at the hydrophobic site in the b' domain of PDI and forms a hydrogen bond with a residue (His138) in tihs domain. They also form multiple weak hydrophobic interactions with various chemical groups of the b' subunit. For the first time, we demonstrate that 1,25-dihydroxyvitamin D3 (1a,25(OH)2 vitamin D3) and paricalcitol inhibit the PDI reductase activity in vitro and their IC50 values are 20.79±1.43 nmol/L and 32.83±3.15 nmol/L respectively. The two compounds can also block the denistrosation activity of PDI.eninfo:eu-repo/semantics/openAccessActivity of EnzymesMolecular DockingParicalcitolProtein Disulfide IsomeraseVitamin D3Amino AcidColecalciferolEstradiolHydrogenParicalcitolProtein Disulfide IsomeraseAmino AcidColecalciferolEstradiolHydrogenJuniferdinParicalcitolProtein Disulfide IsomeraseProtein Disulfide Isomerase ReductaseUnclassified DrugArticleChemical ReactionControlled StudyDenitrosationDrug EffectEnzyme ActivityHydrogen BondHydrophobicityIn Silico DesignIn Vitro StudyMolecular DockingProtein ExpressionProtein Protein InteractionProtein StructureArticle