PubMed İndeksli Yayınlar Koleksiyonu
Permanent URI for this collectionhttps://hdl.handle.net/20.500.12573/397
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Article Identification of Potential Dual HDAC6 and HSP90 Inhibitors for the Treatment of Cancer Using Molecular Docking, Molecular Dynamics and MM/PBSA Studies: A Comprehensive In Silico Study(Bentham Science Publ Ltd, 2026) Yucel, Muhsin Samet; Akcok, IsmailBackground Histone deacetylase 6 (HDAC6) and heat shock protein 90 (Hsp90) are crucial therapeutic targets in cancer research with their interconnected roles in regulating protein homeostasis and cellular processes. The interaction of these proteins within the cytosolic complex plays a critical role in regulating cancer cell survival and progression. Notably, current studies highlight that the simultaneous inhibition of HDAC6 and Hsp90 can produce synergistic effects and offer a promising therapeutic potential for combating malignant cancers.Objective The objective of this study was to explore potential compounds that can inhibit both HDAC6 and Hsp90 proteins.Methods In this study, a number of in-silico computational techniques were employed. A total of 791 molecules, sharing at least 30% similarity with previously identified four HDAC inhibitors, were obtained from the ZINC15 database and subjected to docking on HDAC6 and Hsp90 proteins. The top eight ligands demonstrating the best binding scores against both targets, with panobinostat and ganetespib serving as reference compounds for HDAC6 and Hsp90, respectively, were selected for further analysis. Subsequently, ADME prediction and molecular dynamics simulations were conducted on the selected ligands.Results A detailed molecular docking, molecular dynamics simulations and ADME studies have revealed that ZINC27653366 exhibited the highest inhibitory potential against both Hsp90 and HDAC6 target proteins, making it the most promising inhibitor.Conclusion In conclusion, although additional in vitro and in vivo studies are required for the validation, in silico evaluation of ZINC27653366 may position it as a promising candidate for the treatment of different types of cancers.Article Citation - WoS: 3Citation - Scopus: 4Rapamycin and Niacin Combination Induces Apoptosis and Cell Cycle Arrest Through Autophagy Activation on Acute Myeloid Leukemia Cells(Springer, 2024-12-23) Subay, Lale Beril; Akcok, Emel Basak Gencer; Akcok, Ismail; Gencer Akçok, Emel BaşakBackgroundAcute myeloid leukemia (AML) is a heterogeneous hematological malignancy caused by disorders in stem cell differentiation and excessive proliferation resulting in clonal expansion of dysfunctional cells called myeloid blasts. The combination of chemotherapeutic agents with natural product-based molecules is promising in the treatment of AML. In this study, we aim to investigate the anti-cancer effect of Rapamycin and Niacin combination on THP-1 and NB4 AML cell lines.Methods and ResultsThe anti-proliferative effects of Rapamycin and Niacin were determined by MTT cell viability assay in a dose- and time-dependent manner. The combination indexes were calculated by isobologram analysis. Furthermore, apoptosis was investigated by Annexin-V/Propidium Iodide(PI) double staining and cell cycle distribution was measured by PI staining. The expression levels of autophagy-related proteins were detected by western blotting. The combination of Rapamycin and Niacin synergistically decreased cell viability of AML cell lines. The combination treatment induced the apoptotic cell population of THP-1 and NB4 by 4.9-fold and 7.3-fold, respectively. In THP-1 cells, the cell cycle was arrested at the G2/M phase by 10% whereas the NB4 cells were accumulated at the G0/G1 phase. The combination treatment decreased Akt and p-Akt expression. Besides, the ATG7 expression was reduced by combination treatment on THP-1 cells. Similarly, the ATG5 level was downregulated in NB4 cells. The level of LC3B-II/LC3B-I, which is an indicator of autophagy flux, was upregulated in THP-1 and NB4 cells.ConclusionAlthough further studies are required, the combination of Rapamycin and Niacin combats cell proliferation by inducing cellular apoptosis, cell cycle arrest and autophagy activation.Article Citation - WoS: 13Citation - Scopus: 13Ethacrynic Acid and Cinnamic Acid Combination Exhibits Selective Anticancer Effects on K562 Chronic Myeloid Leukemia Cells(Springer, 2022-05-18) Yenigul, Munevver; Akcok, Ismail; Gencer Akcok, Emel BasakBackground Despite the recent advances in chemotherapy, the outcomes and the success of these treatments still remain insufficient. Novel combination treatments and treatment strategies need to be developed in order to achieve more effective treatment. This study was designed to investigate the combined effect of ethacrynic acid and cinnamic acid on cancer cell lines. Methods The anti-proliferative effect of ethacrynic acid and cinnamic acid was investigated by MTT cell viability assay in three different cancer cell lines. Combination indexes were calculated using CompuSyn software. Apoptosis was assessed by flow cytometric Annexin V-FITC/PI double-staining. The effect of the inhibitors on cell cycle distribution was measured by propidium iodide staining. Results The combination treatment of ethacrynic acid and cinnamic acid decreased cell proliferation significantly, by 63%, 75% and 70% for K562, HepG2 and TFK-1 cells, respectively. A 5.5-fold increase in the apoptotic cell population was observed after combination treatment of K562 cells. The population of apoptotic cells increased by 9.3 and 0.4% in HepG2 and TFK-1 cells, respectively. Furthermore, cell cycle analysis shows significant cell cycle arrest in S and G2/M phase for K562 cells and non-significant accumulation in G0/G1 phase for TFK-1 and HepG2 cells. Conclusions Although there is a need for further investigation, our results suggest that the inhibitors used in this study cause a decrease in cellular proliferation, induce apoptosis and cause cell cycle arrest.Article Discovery and in Silico Characterization of Anatolian Water Buffalo Rumen-Derived Bacterial Thermostable Xylanases: A Sequence-Based Metagenomic Approach(Amer Chemical Soc, 2025-03-18) Kurt, Halil; Kaya, Dilek Sever; Akcok, Ismail; Sari, Ceyhun; Albayrak, Ebru; Velioglu, Hasan Murat; Surmeli, Yusuf; Sever Kaya, DilekThis study involved shotgun sequencing of rumen metagenomes from three Anatolian water buffalos, an exploration of the relationship between microbial flora and xylanases, and in silico analyses of thermostable xylanases, focusing on their sequence, structure, and dynamic properties. For this purpose, the rumen metagenome of three Anatolian water buffalos was sequenced and bioinformatically analyzed to determine microbial diversity and full-length xylanases. Analyses of BLAST, biophysicochemical characteristics, phylogenetic tree, and multiple sequence alignment were performed with Blastp, ProtParam, MEGA11 software, and Clustal Omega, respectively. Three-dimensional homology models of three xylanases (AWBRMetXyn5, AWBRMetXyn10, and AWBRMetXyn19) were constructed by SWISS-MODEL and validated by ProSA, ProCheck, and Verify3D. Also, their 3D models were structurally analyzed by PyMOL, BAN Delta IT, thermostability predictor, What If, and Protein Interaction Calculator (PIC) software. Protein-ligand interactions were examined by docking and MD simulation. Shotgun sequence and Blastp analyses showed that Clostridium (Clostridiales bacterial order), Ruminococcus (Oscillospiraceae bacterial family), Prevotella (Bacteroidales bacterial order), and Butyrivibrio (Lachnospiraceae bacterial family) were found as dominant potential xylanase-producer genera in three rumen samples. Furthermore, the biophysicochemical analysis indicated that three xylanases exhibited an aliphatic index above 80, an instability index below 40, and melting temperatures (T m) surpassing 65 degrees C. Phylogenetic analysis placed three xylanases within the GH10 family, clustering them with thermophilic xylanases, while homology modeling identified the optimal template as a xylanase from a thermophilic bacterium. The structural analysis indicated that three xylanases possessed the number of salt bridges, hydrophobic interactions, and T m score higher than 50, 165, and 70 degrees C, respectively; however, the reference thermophilic XynAS9 had 43, 145, and 54.41 degrees C, respectively. BAN Delta IT analysis revealed that three xylanases exhibited lower B '-factor values in the beta 3-alpha 1 loop/short-helix at the N-terminal site compared to the reference thermophilic XynAS9. In contrast, six residues (G79, M123, D150, T199, A329, and G377) possessed higher B '-factor values in AWBRMetXyn5 and their aligned positions in AWBRMetXyn10 and AWBRMetXyn19, relative to XynAS9 including Gln, Glu, Ile, Lys, Ser, and Val at these positions, respectively. MD simulation results showed that the beta 9-eta 5 loop including catalytic nucleophile glutamic acid in the RMSF plot of three xylanases had a higher fluctuation than the aligned region in XynAS9. The distance analysis from the MD simulation showed that the nucleophile residue in AWBRMetXyn5 and AWBRMetXyn10 remained closer to the ligand throughout the simulation compared with XynAS9 and AWBRMetXyn19. The most notable difference between AWBRMetXyn5 and AWBRMetXyn10 was the increased amino acid fluctuations in two specific regions, the eta 3 short-helix and the eta 3-alpha 3 loop, despite a minimal sequence difference of only 1.24%, which included three key amino acid variations (N345, N396, and T397 in AWBRMetXyn5; D345, K396, and A397 in AWBRMetXyn10). Thus, this study provided computational insights into xylanase function and thermostability, which could inform future protein engineering efforts. Additionally, three xylanases, especially AWBRMetXyn5, are promising candidates for various high-temperature industrial applications. In a forthcoming study, three xylanases will be experimentally characterized and considered for potential industrial applications. In addition, the amino acid substitutions (G79Q, M123E, D150I, T199K, A329S, and G377V) and the residues in the beta 3-alpha 1 loop will be targeted for thermostability improvement of AWBRMetXyn5. The amino acids (N345, N396, and T397) and the residues on the beta 9-eta 5 loop, eta 3 short-helix, and eta 3-alpha 3 loop will also be focused on development of the catalytic efficiency.Article Citation - WoS: 3Citation - Scopus: 3Determination of Promising Inhibitors for N-SH2 Domain of SHP2 Tyrosine Phosphatase: An in Silico Study(Springer, 2024-05-13) Akcok, Emel Basak Gencer; Guner, Huseyin; Akcok, Ismail; Gencer Akçok, Emel BaşakThere are many genes that produce proteins related to diseases and these proteins can be targeted with drugs as a potential therapeutic approach. Recent advancement in drug discovery techniques have created new opportunities for treating variety of diseases by targeting disease-related proteins. Structure-based drug discovery is a faster and more cost-effective approach than traditional methods. SHP2 phosphatase, encoded by the PTPN11 gene, has been the focus of much attention due to its involvement in many types of diseases. The biological function of SHP2 is enabled mostly by protein-protein interaction through its SH2 domains. In this study, we report the identification of a potential small molecule inhibitor for the N-SH2 domain of SHP2 by structure-based drug discovery approach. We utilized molecular docking studies, followed by molecular dynamics simulations and MM/PBSA calculations, to analyze compounds retrieved from the Broad's Drug Repurposing Hub and ZINC15 databases. We selected 10 hit compounds with the best docking scores from the libraries and examined their binding properties in the N-SH2 domain. We found that compound CID 60838 (Irinotecan) was the most suitable compound with a binding free energy value of - 64.45 kcal/mol and significant interactions with the target residues in the domain.