Akçok, İsmail

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https://hdl.handle.net/20.500.12573/2611
Name Variants
Akcok, Ismail
Akçok, Ismail
Job Title
Dr. Öğr. Üyesi
Email Address
ismail.akcok@agu.edu.tr
Main Affiliation
04.01. Biyomühendislik
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Current Staff
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ORCID ID
0000-0002-5444-3929
Scopus Author ID
56705514600
Turkish CoHE Profile ID
280464
Google Scholar ID
v33UJVwAAAAJ
WoS Researcher ID
AAB-8953-2021
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5292_Ismail_Akcok.JPG (6.4 KB)

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11

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18

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3

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1.55

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Chemistryselect2
Molecular Biology Reports2
ACS Omega1
Journal of Experimental and Clinical Medicine (Turkey)1
Molecular Diversity1
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  • Thumbnail Image
    Article
    Citation - WoS: 13
    Citation - Scopus: 13
    Ethacrynic Acid and Cinnamic Acid Combination Exhibits Selective Anticancer Effects on K562 Chronic Myeloid Leukemia Cells
    (Springer, 2022) Yenigul, Munevver; Akcok, Ismail; Gencer Akcok, Emel Basak
    Background 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.
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    Article
    Discovery of New Candidates Targeting the SH2 Domains of Spleen Tyrosine Kinase (Syk) Through in Silico Studies
    (Wiley-VCH Verlag GmbH, 2025) Sansacar, Merve; Sari, Ceyhun; Yucel, Muhsin Samet; Akcok, Emel Basak Gencer; Akcok, Ismail
    Src homology 2 (SH2) domains have become an increasingly popular candidate for researchers to search for novel therapeutics to target different diseases. Spleen tyrosine kinase (Syk) is one of the proteins with two SH2 domains that has a role in the pathogenesis of many diseases. Here, we report the discovery of a promising natural product (NP) inhibitor that targets the N-terminal SH2 (N-SH2) and C-terminal SH2 (C-SH2) domains of Syk simultaneously, through structure-based drug discovery approach. Molecular docking studies, followed by molecular dynamics (MD) simulations and molecular mechanics Poisson-Boltzmann surface area (MM/PBSA) calculations, were utilized to reveal the interactions between NPs from "the COlleCtion of Open NatUral producTs (COCONUT)" database and Syk enzyme. Five natural products that have lowest Scoring and Minimization with AutoDock Vina (SMINA) scores against both SH2 domains of Syk were selected for further studies and compound CNP0265345 has the best binding free energies toward both C-SH2 and N-SH2 of Syk enzyme with -44.54 and -55.98 kcal/mol, respectively. Drug-likeness properties, absorption, distribution, metabolism, and excretion (ADME) and carcinogenicity predictions were also studied. In conclusion, our work highlights a novel drug candidate to target the Syk enzyme of SH2 domains using in silico methods.
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    Article
    Citation - WoS: 2
    Citation - Scopus: 3
    Rapamycin and Niacin Combination Induces Apoptosis and Cell Cycle Arrest Through Autophagy Activation on Acute Myeloid Leukemia Cells
    (Springer, 2025) Subay, Lale Beril; Akcok, Emel Basak Gencer; Akcok, Ismail
    BackgroundAcute 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.
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    Article
    Toward the Design of New Α-Carboline Derivatives Against Anaplastic Lymphoma Kinase (Alk): A Comprehensive in Silico Approach
    (Wiley-VCH Verlag GmbH, 2025) Sari, Ceyhun; Akcok, Ismail
    After the first description of anaplastic lymphoma kinase (ALK) in an anaplastic large cell lymphoma cell line as a nucleophosmin (NPM) fusion partner, ALK and its various fusion partners have been implicated in numerous cancers such as non-small cell lung cancer (NSCLC), anaplastic large cell lymphoma (ALCL), neuroblastoma, and rhabdomyosarcoma. In the last decade, several compounds targeting ALK have been developed and approved by the Food and Drug Administration (FDA). Despite the advances of generations of ALK inhibitors, a recent study highlighted that around half of the ALK-positive NSCLC patients will go through disease progression in response to first-line alectinib, which is a second-generation ALK inhibitor. In this study, we aimed to propose a novel alpha-carboline compound targeting the ALK tyrosine kinase domain to be used against various types of cancer in which ALK fusion proteins may be involved. In this regard, we designed more than 200 alpha-carboline derivatives and investigated their binding properties against ALK tyrosine kinase by using in silico protocols consisting of molecular docking studies, molecular dynamics simulations, MM/PBSA binding free energy calculation, and essential dynamics analysis. Considering the obtained results, we developed two promising candidates, compounds 208 & 209 with -9.05 and -9.80 binding energies, respectively, which demonstrated improved binding profiles over the course of a 300 ns simulation.
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    Article
    Anticancer Effect of Ethanolic Yellow Hawthorn Extract on Chronic Myeloid Leukemia Cells and Acute Myeloid Leukemia Cells
    (Ondokuz Mayis Universitesi, 2025) Arslan, Ayşe Nur; Akçok, Ismail
    Cancer is a disease characterized by abnormal cell growth and invasion and metastasis of these cells to other tissues or organs of the body. Natural products have been used for centuries as drugs or in drug development, especially for the treatment of cancer. Besides, extracting natural products with several bioactive compounds has a promising effect on cancer treatment. In this study, we aimed to investigate the anticancer effect of the ethanolic extract of yellow hawthorn fruits on K562 (Chronic Myeloid Leukemia) and MOLM-13 (Acute Myeloid Leukemia) cell lines. The antiproliferative effect of the ethanolic extract of yellow hawthorn fruits was investigated in time-and dose-dependent manners. The Annexin-V/Propidium Iodide (PI) double staining was used to examine the apoptosis. Furthermore, cell cycle analysis is conducted by PI staining. The cell viability of K562 and MOLM-13 cell lines was significantly reduced by the ethanolic extract of yellow hawthorn fruits with IC50 values of 9144 µg/mL and 3515 µg/mL in 48-hour incubation time, respectively. Moreover, the results showed that the ethanolic extract of yellow hawthorn fruits caused an increased apoptosis by 12.7-and 8.87-fold changes in K562 and MOLM-13 cell lines compared to control groups, respectively. Ethanolic extract of yellow hawthorn fruit has reduced cell proliferation, induced apoptosis and arrested the cell cycle at G0/G1 phase by 71% in MOLM-13 and at G2/M phase by 80.3% and G0/G1 phase by 38.2 % in K562 cells. Further studies should be conducted to elucidate the mechanism of the effect of yellow hawthorn fruit on these cancer cells. © 2025 Elsevier B.V., All rights reserved.
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    Master Thesis
    Akut Miyeloid Lösemide SYK Enziminin Hedeflenmesi: Bi 1002494'ün In Silico İlaç Yeniden Konumlandırımı ve İşlevsel Doğrulaması
    (2025) Tekden, Şevket Oğuzhan; Akçok, Emel Başak Gencer; Akçok, İsmail
    Akut miyeloid lösemi (AML), kemik iliğindeki miyeloid hücrelerin denetimsiz biçimde büyümesi ve çoğalmasıyla tanımlanan bir kan kanseri türüdür. Sağaltım için radyoterapi gibi yöntemlere başvurulsa da bunların sınırlı başarı oranlarına iye olması, başka hedefe yönelik sağaltım çalışmalarını zorunlu kılmaktadır. AML ile ilişkili olduğu bilinen dalak tirozin kinaz (Syk) enzimi hücre içi sinyal iletiminde önemli bir enzimdir. Syk'de oluşabilecek bozukluklar, AML'nin ortaya çıkması üzerinde oldukça etkilidir. Bu nedenle Syk odaklı kullanılan inhibitörler AML açısından umut vericidir. Çalışmada opnMe veri tabanındaki aday molekül üzerinde in silico moleküler kenetleme gerçekleştirilmiş ve yüksek bağlanma eğilimi gösteren 'BI 1002494' Syk inhibitörü seçilerek, hedefe yönelik bir 'ilaç yeniden konumlandırma' gerçekleştirilmiştir. Syk'nin katalitik bölgesi, Escherichia coli bakterilerinde rekombinant olarak üretilmiş ve His-işaretli Ni-NTA afinite kromatografi yöntemi ile katalitik bölge saflaştırılmıştır. Saflaştırılan proteinin varlığı Western Blot (WB) yöntemiyle doğrulanmış ve Termal Kayma Deneyi (TSA) ile inhibitörün protein üzerindeki moleküler düzeyde etkileri araştırılmıştır. Hücresel etkinlik tespiti için, MOLM-13 ve K562 hücre hatlarında MTT sitotoksisite deneyleri gerçekleştirilmiş, BI 1002494'ün hücre çoğalmasını baskıladığı, elde edilen verilerin FDA onaylı Syk inhibitörü R406 ile benzer düzeylerde olduğu gözlemlenmiştir. Sonuçlar, BI 1002494'ün AML'ye karşı olası sağaltıcı bir Syk inhibitörü olduğunu göstermektedir. Bu çalışma, ilaç yeniden konumlandırma kapsamında hedefe odaklı, bilgisayar tabanlı sağaltım yaklaşımlarına değerli katkılar sunmaktadır.
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    Article
    Discovery and in Silico Characterization of Anatolian Water Buffalo Rumen-Derived Bacterial Thermostable Xylanases: A Sequence-Based Metagenomic Approach
    (Amer Chemical Soc, 2025) Kurt, Halil; Kaya, Dilek Sever; Akcok, Ismail; Sari, Ceyhun; Albayrak, Ebru; Velioglu, Hasan Murat; Surmeli, Yusuf
    This 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.
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    Master Thesis
    Design and Identification of Novel Candidates Against the Tyrosine Kinase Domain of ALK by Comprehensive in Silico Approaches
    (2025) Sarı, Ceyhun; Akçok, İsmail
    Anaplastik büyük hücreli lenfoma hücre hatlarında füzyon protein ortağı olarak keşif edilen Anaplastik Lenfoma Kinaz'ın (ALK), keşifinden bu yana ALK çeşitli füzyon ortakları ile çok sayıda kanserde rol oynadığı ortaya çıkmıştır. Rol oynadıkları kanser şu şekilde sıralanabilir: küçük hücreli olmayan akciğer kanseri (NSCLC); anaplastik büyük hücreli lenfoma (ALCL); nöroblastom; rabdomiyosarkom; vb. Son yılda, ABD Gıda ve İlaç Dairesi (FDA) ALK'yi hedefleyen birçok bileşik onay almıştır. Bu gelişmelere rağmen, yakın zamanda yapılan bir çalışma ALK pozitif NSCLC hastalarının yaklaşık yarısının hastalık ilerlemesi yaşanacağını vurgulanmıştır, başlangıç tedavisi olan Alectinib, ikinci nesil ALK inhibitörü ve üçüncü nesil ALK inhibitörü Lorlatinib rağmen. Bu noktaları göze alarak, bu çalışma ALK'nin tirozin kinaz alanını hedefleyebilecek yeni bileşikler keşfetmek ve geliştirmek için iki farklı yola odaklanmıştır. İlk yaklaşım olarak 200'den fazla α-carboline türevi tasarladık. Devamında moleküler yanaştırma (Docking), moleküler dinamik (MD) simülasyonlarını MM/PBSA ile serbest bağlanma enerjisi hesaplamalarından oluşan in silico protokolleri kullanarak tasarımlarımızın hedefimize karşı bağlanma özelliklerini araştırdık. İkinci yaklaşım olarak büyük bir doğal ürün veritabanını aynı amaca yönelik yeni bir ilaç adayı keşfetme adına sanal olarak taradık. Devamında bağlanma özelliklerini ilk yaklaşımda kullanılan yöntemlerle inceledik. Elde edilen bütün sonuçları göz önünde bulundurarak, sonuçlar takip eden şekilde özetlenebilir. Üç umut verici ilaç adayı aralarından yükselmiştir test edilen bileşikler arasında, bileşik 208, 209 ve CNP0106316.1. Serbest bağlanma enerjileri ise sırasıyla -9.08, -9.80 ve -11.6 kcal/mol olarak bulunmuştur. Ek olarak, ismi geçen bileşikler ilgili MD simülasyonlarında stabil bağlanma profilleri göstermişlerdir.
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    Master Thesis
    Kanser Tedavisi için HDAC6 ve ALK'yi Hedef Alan İkili Hsp90 İnhibitörlerinin İn Siliko Keşfi
    (2025) Yücel, Muhsin Samet; Akçok, İsmail
    Isı şoku proteini 90 (Hsp90), histon deasetilaz 6 (HDAC6) ve anaplastik lenfoma kinaz (ALK), protein homeostazını ve hücresel süreçleri düzenlemedeki birbiriyle bağlantılı rolleriyle kanser araştırmalarında önemli terapötik hedeflerdir. Bu proteinlerin sitozolik kompleks içindeki etkileşimi, kanser hücresinin hayatta kalmasını ve ilerlemesini düzenlemede kritik bir rol oynar. Özellikle, güncel çalışmalar, Hsp90-HDAC6 veya Hsp90-ALK'nin eş zamanlı inhibisyonunun sinerjik etkiler üretebileceğini ve kötü huylu kanserlerle mücadele için umut verici bir terapötik potansiyel sunabileceğini vurgulamaktadır. Bu tezin amacı, hem Hsp90-HDAC6 hem de Hsp90-ALK proteinlerini inhibe edebilen potansiyel bileşikleri keşfetmektir. Bu amaçla, bir dizi in-silico hesaplama tekniği kullanıldı. Hsp90-HDAC6 bölümü için, ZINC veri tabanından benzerlik filtrasyonu ile 791 molekül ve COCONUT veri tabanından 5 kriterli Lipinski kuralı ile 361.179 bileşik Hsp90-ALK bölümü için seçildi. Seçilen ligandlar sorumlu protein yapıları üzerinde yerleştirmeye tabi tutuldu. Her iki hedefe karşı en iyi bağlanma skorlarını gösteren en iyi ligandlar, referanslarıyla birlikte daha ileri analizler için kullanıldı. Daha sonra, seçilen ligandlar üzerinde ADME tahmini ve moleküler dinamik simülasyonları gerçekleştirildi. Tüm analizlerin tamamlanmasının ardından, ayrıntılı bir in-silico değerlendirmesi, Hsp90-HDAC6 bölümünde ZINC27653366'nın ve Hsp90-ALK bölümünde CNP0264442.1'in en yüksek inhibitör potansiyelini gösterdiğini ve bunları en umut verici inhibitörler haline getirdiğini ortaya koydu.
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    Master Thesis
    Histon Deasetilaz İnhibisyonu ve Otofaji Modülasyonunun Kolanjiokarsinoma Hücrelerine Etkisi
    (Abdullah Gül Üniversitesi, Fen Bilimleri Enstitüsü, 2022) Yenigül, Münevver; Yenigül, Münevver; Akçok, Emel Başak Gencer; Akçok, İsmail
    Cholangiocarcinoma (CCA), also known as biliary tract cancer, is a heterogeneous group of malignancies formed by the differentiation of epithelial cells in the biliary tract. CCA is the second most common primary liver tumor and it has both an increasing rate and high mortality worldwide with its late diagnosis, refractory type, and aggressiveness. The effects of autophagy modulators and HDAC inhibitors in CCA are not fully known. This study is proposed a novel treatment approach with the combinational therapy of autophagy and HDAC inhibitors for CCA patients. In results obtained with alone HDACis, alone autophagy modulators, and combinations of HDACis and autophagy modulators, Nocodazole from autophagy modulators and MS-275 and Romidepsin from HDAC inhibitors showed a better synergistic effect on the TFK-1 and EGI-1 cell lines of the cholangiocarcinoma. In cell cycle analysis of the combination, was achieved arrest at the S phase and G2/M phase. In conclusion, this study highlights the important combination of HDAC inhibitors and autophagy modulators, which is a promising therapy in CCA. Keywords: Cholangiocarcinoma, HDAC inhibitors, Autophagy modulators, Combination therapy