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    Computational Study of Coumarin Compounds as Potential Inhibitors of Casein Kinase 2: DFT, 2D-QSAR, ADMET and Molecular Docking Investigations
    (Taylor & Francis Ltd, 2024) Chennai, Hind Yassmine; Belaidi, Salah; Ouassaf, Mebarka; Sinha, Leena; Prasad, Onkar; Serdaroglu, Goncaguel; Chtita, Samir
    Casein kinase 2 (CK2) is an ubiquitous, essential, and highly pleiotropic protein kinase whose abnormally high constitutive activity is suspected to underlie its pathogenic potential in neoplasia and other diseases. Recently, there has been a notable increase in interest in the use of casein kinase 2 (CK2) inhibitors to improve the treatment of a specific form of cancer while minimizing the risk of undesirable side effects. Recently, using different virtual screening approaches, we have identified several novel CK2 inhibitors. In particular, we have discovered that the coumarin moiety can be considered an attractive CK2 inhibitor scaffold. In the present work, quantitative structure-activity relationship (QSAR) analysis has been employed to envisage the inhibitory effects of 32 coumarin derivatives on the CK2 protein. The most efficient model is found by using multiple linear regression (MLR). Its capability is considered by the external and internal validation values found (R2 = 0.884, Q2cv = 0.822, R2pred = 0.821, and R2p = 0.811), which aligned well with Tropsha and Golbraikh's approach. The highest docking score founded for the newly designed coumarins is -7.50 kcal mol-1, which indicates that candidates can bind to the CK2 receptor with greater affinity. Based on the results of the ADMET properties and drug similarity analyses, a DFT investigation was conducted to confirm the stability of the newly explored compounds. It appears that the most stable complexes are those of compound with the highest binding affinity with a lower risk of toxicit & eacute;.
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    Effect of azomethine group containing compounds on gene profiles in Wnt and MAPK signal patterns in lung cancer cell line: In silico and in vitro analyses
    (Elsevier, 2023/3/5) Agbektas, Tugba; Zontul, Cemile; Ozturk, Alpaslan; Huseynzada, Alakbar; Ganbarova, Rana; Hasanova, Ulviyya; Cinar, Gulcihan; Tas, Ayca; Kaya, Savas; Chtita, Samir; Silig, Yavuz
    The main aims of anticancer drug development studies is to reduce the toxicity of the developed com- pound and maximize the effectiveness, as well as the discovery of artificial and natural compounds. In recent years, scientists have accelerated their research on new molecules with anticancer activity. In re- cent years, new drugs containing the azomethine group are thought to be promising in the treatment of cancer. In this study, firstly, the synthesis of azomethine group-containing compounds, i.e. Schiff bases, which was designed theoretically, was carried out. Secondly, the application of the newly synthesized compounds 1, 2, 3 and 4 to the lung cancer cell line (A-549), followed by the determination of their anticancer activities, and finally the Wnt signaling pathway ( CSNK1A1, CTNNB1 ), MAPK signaling path- way ( DUSP1, DUSP2, DUSP4 and DUSP10 ) genes on expression levels was investigated. The compounds synthesized in our study were characterized by 1H and 13C NMR spectroscopy methods. The anticancer activities of the new synthesized molecules were determined in the A-549 lung cancer cell line using the MTT method. Expression levels of Wnt signaling pathway ( CSNK1A1, CTNNB1 ) and MAPK signaling path- way ( DUSP1, DUSP2, DUSP4 and DUSP10 ) genes were determined by RT-PCR method. In addition, A-549 cells were evaluated in terms of biochemical parameters. In addition to experimental studies, theoretical studies were carried out. Molecular docking results were found to be compatible with the experiments. Compounds 1, 2, 3 and 4 applied to cell line A-549 showed the highest activity after 72 h of incubation. As a result, it was determined that compounds 2 and 4 increased the expression of CTNNB1 and DUSP10 genes compared to the control group. It was determined that compound 4 increased the expression level of CSNK1A1, CTNNB1, DUSP1, DUSP2, DUSP4 and DUSP10 genes compared to other groups. A-549 lung can- cer cells showed a 70% reduction in GST levels in compound 1, while a 96% reduction in CAT levels in compound 1 compared to the control group. Molecular docking calculations supported the Experimental observations. Calculated binding energies provided important clues about drug efficiencies of molecules studied.
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    Experimental and theoretical insights about the effect of some newly designed azomethine group?contained macroheterocycles on oxidative stress and DNA repair gene profiles in neuroblastoma cell lines
    (Elsevier, 2023/8/5) Cinar, Gulcihan; Agbektas, Tugba; Huseynzada, Alakbar; Aliyeva, Gunel; Aghayev, Mirjavid; Hasanova, Ulviyya; Kaya, Savas; Chtita, Samir; Nour, Hassan; Tas, Ayca; Silig, Yavuz
    We report herein the synthesis of new azomethine group containing forty-, sixty-eight- and seventy- two-membered macroheterocyclic compounds and the investigation of their activity against the neurob- lastoma cell line. The synthesis of targeted compounds was done by condensation of dialdehydes with polyamines and their structures were investigated by 1 H and 13 C NMR and MALDI MS methods. Anti- cancer activity of these newly synthesized molecules was studied in the neuroblastoma (SH-SY5Y) cell line at eight different concentrations (1–100 μg/ml) for 24 h, 48 hrs and 72 h by MTT method. In ad- dition to it, oxidative stress (GPX1, PRDX1, CAT, SOD1, NQO1) and DNA repair (ATR, ERCC1, CDKN1A, PRKDC) gene profiles were also investigated by RT-PCR method. It was found that all synthesized compounds showed the highest activity after 72 h of incubation. PRDX1 gene expression in the case of all investi- gated compounds was found to be higher than the control group, whereas ABCB1 (MDR) gene expression increased only in the case of molecule 1. Results also demonstrate that the expression levels of GPX and SOD1 genes were high in the case of molecule 2, whereas molecule 1 manifested low expression levels of ERCC1, ATR, CDKN1A, PRKDC, GPX1, ABCB1(MDR), CAT, SOD1 and NQO1 genes. Along with experimen- tal studies, theoretical studies were also carried out. The String v11 program was used to determine the interaction of proteins involved in oxidative stress and DNA repair mechanisms with other proteins. The results of the molecular docking analysis were found to be in good agreement with the experiments.
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    Metal Complexes of a Thiosemicarbazone with Heterocyclic Bases as Coligands: Spectral Characterization, Crystal Structures, DFT and In silico Docking Studies
    (Springer/Plenum Publishers, 2024) Mathews, Nimya Ann; Sithambaresan, M.; Kaya, Savas; Chtita, Samir; Kurup, M. R. Prathapachandra
    Copper(II) and zinc(II) complexes, [Cu(esct)(4-pico)] (1), [Zn(esct)(5,5 '-dmbipy)]center dot H2O (2), [Cu(esct)(5,5 '-dmbipy)] (3), (where H(2)esct = 3-ethoxysalicylaldehye-N4-cyclohexylthiosemicarbazone) were synthesized by reacting copper acetate/zinc acetate with the thiosemicarbazone derivative (H(2)esct) along with heterocyclic bases. The thiosemicarbazone forms doubly deprotonated anions in all the complexes to coordinate via thiolate S, azomethine N and phenolate O atoms. The complexes were characterized by various spectroscopic techniques like infrared, UV-vis, 1H NMR and EPR spectra. The single crystal XRD studies confirmed the structures. All the three complexes got crystallized in triclinic space group P (1) over bar Complexes are found to have four, five and six coordination around the metal center. The importance of van der Waals interactions in them is explained by Hirshfeld surface analysis. We have used Density Functional Theory (DFT) methods and optimized ground states of the studied complexes using the Gaussian 09 package. Electrostatic potential plots of complexes were investigated. Further, docking studies were carried out with various Epidermal Growth Factor Receptor (EGFR) enzymes. [GRAPHICS] .
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    Screening of Novel 1,2,4-triazine Clubbed 1,2,3-triazole Derivatives as Α-glucosidase Inhibitors: In Silico Study
    (Bentham Science Publishers, 2025) Chaturvedi, Neha; Bhattacharya, Sushanta; Asati, Vivek; Chtita, Samir; Kaya, Savaş; Almehizia, Abdulrahman A.; Dubey, Raghvendra
    Introduction: A new set of 1,2,4-triazine combined 1, 2, 3-triazole hybrids were designed computationally for predicting anti-diabetic potential. All the derivatives taken for study exhibited excellent anti-diabetic potential with significant IC50 values. Methods: The present research includes the development of pharmacophore models, 3D QSAR, virtual screening, molecular docking, and evaluation of models based on certain criteria. The DHRRR_1 showed the best pharmacophore model with a survival score of 5.9937. The 3D QSAR analysis developed a model with the values of R2 = 0.9714 and Q2 = 0.7202. The binding pose and affinity of the most potent compound, 10c, in the active site of α-glucosidase was investigated using in-silico molecular docking analysis. Results: It was observed that compound 10c demonstrated promising binding affinity with a score of -8.078 kcal/mol and exhibited binding interaction with the essential amino acids ASN301 and LEU227. There were five compounds (1-5) that showed significant binding affinity towards the target comprising active amino acids (ASH202, ASP333 and VAL335). The molecular dynamic study showed the stability of ligand-protein binding interactions. Conclusion: The results of the present investigation can accelerate the optimization and reformation of the latest anti-diabetic agents that target the α-glucosidase. © 2025 Bentham Science Publishers.
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    Screening of Novel Hydroxamic Acid Derivatives as ASM Inhibitors for the Treatment of Depression
    (Wiley-V C H Verlag Gmbh, 2024) Gupta, Shankar; Asati, Vivek; Ali, Amena; Chtita, Samir; Kaya, Savas; Ali, Abuzer
    In the present work, we performed a computational study on hydroxamic acid containing compounds as acid sphingomyelinase (ASM) inhibitors. The study starts from the development of 3D-QSAR and pharmacophore models, which were further taken as a source for the enumeration and virtual screening study. The 3D-QSAR results showed the best statistical model with Q2, R2, and R2 scrambling values of 0.7175, 0.9019, and 0.7128, respectively. The pharmacophore hypothesis generated one of the best hypotheses including five features such as 2 aromatic rings, 2 hydrogen bond donors, and 1 hydrogen bond acceptor. The enumeration study paved the path in the discovery of novel compounds where pharmacophore hypothesis and 3D QSAR study data was used for the identification of novel compounds. Compound 9f_20 showed good docking score -11.399 and binding interactions with amino acids HIP317, ASN316, GLH386, Zn701, Zn702, HIP317, and HIP280 required for ASM inhibitory activity. The virtual screening study was performed on the basis of developed pharmacophore ADDRR_1 where ZINC000013941849 showed good binding interactions with receptor including amino acids Zn701, Zn702, HIP280, LYS103, HIP317, ASN316, and ILE487. ZINC000013941849 with docking score -13.101. The screened compounds may be taken for the further development of novel antidepressant agents. The present work consists of a computational study on hydroxamic acid-containing compounds as sphingomyelinase (ASM) inhibitors. The study starts from the development of 3D-QSAR and pharmacophore models, which are further taken as a source for the enumeration and virtual screening study. The screened compounds may be taken for the further development of novel antidepressant agents. image