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- MakaleYalnız künye2026Scopus SJRQ3Investigating the interactions of Axitinib, a tyrosine kinase inhibitor, with DNA: experimental studies, molecular docking, and molecular dynamics simulations
Şenel, Pelin; Faysal, Abdullah Al; Agar, Soykan; Yurtsever, Mine; Gölcü, Ayşegül
Axitinib is an oral medication classified as a second-generation tyrosine kinase inhibitor. It serves as a primary treatment for metastatic renal cell carcinoma (RCC) due to its strong affinity for DNA, which leads to the disruption of the double helix structure. This disruption ultimately halts the cell cycle and induces senescence and mitotic catastrophe in RCC cells. Consequently, investigating the mechanism by which Axitinib binds to DNA is essential for comprehending its pharmacodynamic properties and for the advancement of more effective DNA-binding therapeutics. The present study aimed to examine the interaction between Axitinib and DNA through various analytical techniques, including UV-Vis spectroscopy, thermal denaturation assays, electrochemical methods, and fluorescence emission spectroscopy. According to the electrochemical studies, the binding constant (Kb) for Axitinib was calculated to be (5.13 ± 0.28) × 104, suggesting the potential for groove binding. This finding was further supported by in-silico analyses, where molecular docking and molecular dynamics simulations indicated that the drug selectively binds to the DNA minor groove through partial intercalation, forming new hydrogen bonds with its functional groups while separating the guanine and cytosine base pairs.
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İncele - MakaleYalnız künye2026Scopus SJRQ2Transition-metal coordination modulates predicted DNA groove recognition and nucleobase contacts in oligohistidine complexes
Agar, Soykan; Yildiz, Alparslan Numan; Yurtsever, Mine
Histidine-rich peptides are widely used in affinity-based purification because imidazole donors can coordinate transition-metal ions. To examine how fixed metal-coordination models may alter the predicted DNA-contacting behavior of a histidine hexamer, a fully in silico comparison was performed using metal-free His6 and the tri-metal model complexes [Zn3(His6)]6+, [Ni3(His6)]6+, and [Cu3(His6)]6+ against the canonical B-DNA dodecamer 1BNA [d(CGCGAATTCGCG)]. The formulas denote the neutral-terminal/neutral-imidazole computational representation used for docking and molecular dynamics (MD), rather than a claim concerning the dominant solution-phase species. Molecular docking and MD simulations were used to compare predicted groove localization, recurrent nucleobase-associated contacts, hydrogen-bond patterns, relative docking scores, and trajectory-based structural persistence. Within the examined 1BNA model, metal-free His6 produced a dominant major-groove pose with adenine-associated contacts and a Vina docking score of −8.9 kcal/mol. The tri-metal coordination models produced dominant minor-groove poses with guanine-associated contacts, with relative docking scores of −9.5, −13.5, and −10.8 kcal/mol for the Zn(II), Ni(II), and Cu(II) models, respectively. The Ni(II)- and Cu(II)-containing models also displayed lower RMSD levels than the metal-free complex over the sampled trajectories. These observations are restricted to the defined computational models and the 1BNA sequence; they do not establish experimental binding affinities, universal nucleobase selectivity, or solution-phase metal speciation. The work provides a hypothesis-generating comparison that may guide future experimental investigation of metal-coordinated oligohistidine-DNA interactions.
- MakaleYalnız künye2025Scopus SJRQ2An in-depth study of clofarabine's binding mechanism to DNA: A thorough experimental and theoretical investigation
Agar, Soykan; Senel, Pelin; Al Faysal, Abdullah; Gölcü, Aysegul; Yurtsever, Mine
The interaction of medicinal compounds with nucleic acids is a critical challenge in drug development. This research focused on the binding dynamics of clofarabine (CLO), an antineoplastic agent, with fish sperm DNA (dsDNA) under conditions that simulate the physiological environment at a pH of 7.4. The investigations employed multiple techniques, including fluorescence and UV spectroscopy, thermal denaturation analysis, viscosity measurements, electrochemical assessments, and molecular docking studies to elucidate these binding interactions. The binding constant (Kb) for the interaction between CLO and dsDNA, as determined from the Benesi-Hildebrand plot, was found to be 2.74 x 104 at a temperature of 298 K. The entropy (Delta S) and enthalpy (Delta H) changes associated with this binding interaction were measured as + 43.08 J mol- 1 K- 1 and -12.44 kJ mol-1, respectively. These values indicate that the predominant forces driving the binding interaction are primarily due to hydrogen bonding. Studies using the ethidium bromide and the Hoechst probe showed that CLO does not bind to dsDNA intercalatively. Findings obtained through UV-Vis absorption spectroscopy, competitive binding assays, and viscosity assessments indicated that CLO associates with dsDNA by binding within the minor groove. Molecular docking analyses demonstrated that CLO is accommodated within the ATrich segment of the minor groove, with significant hydrogen bonding interactions occurring between CLO and dsDNA. These findings may offer valuable perspectives for elucidating the mechanisms underlying the toxicity, resistance, and adverse effects associated with CLO.
AtıfWoS3OpenAlex4İncele - MakaleAçık Erişim2024High Performance Liquid Chromatography-Tandem Mass Spectrometric determination of carcinogen nitrosamine impurities from pharmaceuticals and DNA binding confirmation aided by molecular docking application
Danie, Ibrahim; Agar, Soykan; Yurtsever, Mine; Uenal, Durieehvar oezer
Background and Aims: Nitrosamines are amine compounds attached to a nitroso group. The reaction of amines and nitrosating agents forms nitrosamines. Nitrosamine impurities are classified as Class 1 based on the carcinogenicity and mutagenicity data by ICH M7 (R1). The recent discovery of nitrosamines in some pharmaceutical products has caused concern. Nitrosamines are carcinogenic, so it is necessary to determine the possible nitrosamines in pharmaceutical products. Methods: An Inertsil ODS-3, (4.6x250 mm, 5 mu m) column was used for separation. A triple quadrupole mass detector with electrospray Ionisation (ESI) was used for detection. Multiple reaction monitoring (MRM) was used for quantification. The transition ions are 75.1 > 43.3 for NDMA and 103.0 > 75.1 for NDEA. The calibration curves consist of 5 concentration levels, including NDMA and NDEA (5, 10, 50, 100, 150 ng/mL). The mean r2 value was 0.997 for NDMA and 0.999 for NDEA. For NDMA and NDEA, LOD: 2 ng/mL, LOQ: 5 ng/mL. Results: Comprehensive in silico and in vitro results indicate that the method has good accuracy and precision. Conclusion: DNA binding interactions of the molecules NDMA and NDEA, were investigated through the molecular docking and molecular dynamics methods. Molecular Docking simulations showed that these small organic molecules have high-affinity scores and strongly bind to the minor groove of the hDNA via strong hydrogen bonds.
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