NSO has attracted great interest as a medicinal and possible preventive agent in recent years due to its numerous stated advantages. The negative effects of DOX on kidneys were examined as biochemical it was aimed to evaluate the possible effects of NSO when faced with DOX-related kidney damage. As a result, it is seen that NSO treatment significantly approaches the results of the control group in terms of PK activity. The results obtained raise the possibility that NSO could be used as an adjuvant therapy to protect organs from DOX-induced oxidative stress. Yilmaz et al. in their study aiming to evaluate the effect of propolis on PK, a key enzyme in glycolysis, and superoxide dismutase, an antioxidant enzyme, on DOX-induced toxicity in different tissues that there was a decrease in PK activities in many tissues including kidney tissue after DOX was applied at the same dose as in the current study. In a study examining changes in pyruvate kinase enzyme activities in the liver and kidney tissues of rats induced with streptozotocin, it was determined that PK activities in the kidney tissue decreased statistically insignificantly on the 3rd day of diabetes. In the same study, it was determined that PK activity decreased in the liver tissue after diabetes
19,31. In this study, PK activity decreased after DOX application, and this decrease may be due to a decrease in pyruvate kinase synthesis. Pyruvate kinase, one of the enzymes of the glycolytic pathway, is a key enzyme in glucose metabolism. This should also suggest that DOX used in cancer treatment may cause a decrease in the gene transcription level of the PK enzyme.
In the previous study, the interaction area of PK (PDB ID: 1A3X) and its cocrystal ligand, 2-phosphoglycolic acid (PDB ID: PGA), was revealed. Hydrogen bonds were observed between ARG49, GLY265, and THR298 between PGA and the macromolecule. It was also emphasized that it was observed to form a metal coordination bond with MN100132.
When the docking results were examined, it was seen that the components detected in the fixed oil interacted with MN1001, which was seen to be important in terms of interaction, but the essential oil components did not interact. When the estimated inhibition values on PK were examined here, it was estimated that fixed oil components would inhibit at the nanomolar level and essential oil components would inhibit at the micromolar level. In their recent study on pyruvate kinase, Yilmaz et al. reported that caffeic acid phenethyl ester (CAPE) makes ASP266 hydrogen bonds similar to Linoleic acid (a)19.
The fact that the molecular volumes of the fixed oil components are relatively large and the essential oil components are relatively small may be effective in these results. Especially when the dock scores of Linoleic acid (a) were examined, it was perceived that it would have the highest affinity for the PK (Table 3). Also, it showed that Palmitic acid (c) and Thymoquinone (e) were one of the selected compounds with the best pose on the PK, for fixed and essential oils respectively (Figure 2-5).
Looking at the SwissAdme Boiled Egg model, no results were obtained for Linoleic acid (a). Only Oleic acid (b) was observed in the white zone, which stands for human gastrointestinal absorption (HIA). Palmitic acid (c), p-Cymene (d), Thymoquinone (e), and Carvacrol (f) were seen in the yellow region, which means passage through the blood-brain barrier. It was observed that all selected components of NSO were in full compliance with the Lipinski rules (except a). In particular, Thymoquinone (e) was found to be compatible with the rules of Lipinski, Ghose, Veber, and Egan, excluding Muegge. None of the compounds complied with the Muegge rule under the drug-likeness heading in the ADME predictions tables. Considering ADME predictions compounds b, c, d, e, and f had good pharmacokinetic profiles, but compound a was not found any drug-likeness properties (Table 4-5, Figure 6).
When the DOX group was compared with the control group, a decrease in PK activity was found, and a significant difference was found in PK activity. Moreover, it was determined that PK activity in the group administered DOX together with NSO increased statistically significantly compared to the DOX group and the values approached the control group values. When we look at the molecular docking studies conducted to elucidate this in vivo effect of NSO, it is thought that the dock score of especially the fixed oils contained in NSO is higher, but this dock score difference between the fixed and volatile oil components may depend on the structural volumes of the components. When molecular docking poses and interacting residues were evaluated together, it was concluded that the essential oil components may be more active. The results of the essential oil components with higher drug similarity rates in ADME predictions support these assumptions.
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