Browsing by Author "Kuzu, B."

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Exploring Natural Compounds Targeting Pd-L1 and Stat3: Toxicogenomic Analysis, Virtual Screening, Molecular Docking, Admet Evaluation, and Biological Activity Prediction
(Bentham Science Publ Ltd, 2025) Karakus, F.; Kuzu, B.; Kostekci, S.; Tuluce, Y.
BACKGROUND: One of the most important targets in cancer immunotherapy is programmed cell death ligand 1 (PD-L1). Monoclonal antibodies developed for this target have disadvantages due to their low bioavailability and some immune-related adverse effects. Additionally, small molecules targeting PD-L1 are still in the experimental stage. At this point, discovering non-toxic natural compounds that directly or indirectly target PD-L1 is essential. In this in silico study, a comprehensive literature search was conducted to identify publications reporting the master regulator of PD-L1, which was suggested as a Signal Transducer and Activator of Transcription 3 (STAT3). The relationship between STAT3 and PD-L1 was further investigated through bioinformatic analysis. METHODS: Subsequently, natural compounds targeting PD-L1 and STAT3 were screened, and compounds with suitable toxicity profiles were docked against both PD-L1 and STAT3. Following molecular docking, the selected molecules underwent DNA docking, ADMET profile analysis, and in silico assessment of biological activities. The relationship between PD-L1 and STAT3 was determined in 52 out of the 453 articles, and it was further demonstrated in genegene interactions. Following the virtual screening, 76 natural compounds were identified, and after pre-filtering based on physicochemical properties, drug-likeness, and ADMET profiles, 29 compounds remained. RESULTS: Subsequent docking revealed that two compounds, 6-Prenylapigenin, and Gelomulide J, persisted. ADMET and biological activity prediction results suggested that 6-Prenylapigenin is non-toxic and has the potential to inhibit PD-L1 and STAT3 in silico. The present study highlights that STAT3 serves as the master regulator of PD-L1, and it further suggests that 6- Prenylapigenin exhibits the potential to modulate PD-L1 and/or STAT3. CONCLUSION: This finding could pave the way for the development of small molecules designed to block the PD-1/PD-L1 interaction by silencing the PD-L1 and/or STAT3 genes or reducing protein levels. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.
In Silico and In Vitro Anticancer Effects of Caffeic Acid Phenethyl Ester on Pancreatic Adenocarcinoma Cells
(Society of Pharmaceutical Sciences of Ankara (FABAD), 2023) Tanriverdı, Z.; Kuzu, B.; Eyol, E.; Karakuş, F.
Pancreatic adenocarcinoma is an aggressive and fatal malignancy due to the lack of early diagnosis and poor therapeutic response. At this point, determining the anticancer potential of non-toxic natural compounds is essential. Caffeic acid phenethyl ester is a bioactive compound with different activities. In this study, the toxicity of caffeic acid phenethyl ester was estimated by in silico methods in 14 pancreatic cancer cells, and its anticancer activity was evaluated in rat adenocarcinoma cells. According to the in silico results, caffeic acid phenethyl ester had anticancer properties without causing severe toxicity. Subsequently, we investigated the effects of caffeic acid phenethyl ester on rat pancreatic cancer (ASML) cells. Caffeic acid phenethyl ester reduced ASML cell viability by up to 27% in a dose-(5, 10, 20, 40, and 80 μM) and time-dependent (24, 48, and 72 h) manner. In the scratch assay, only 80 μM caffeic acid phenethyl ester statistically considerably inhibited ASML cell migration at 24 h. On the other hand, at 48 hours, all doses of caffeic acid phenethyl ester statistically remarkably decreased cell migration. Caffeic acid phenethyl ester also decreased ASML colony numbers at 5 μM and 10 μM compared to the control and completely suppressed colony formation at ≥ 20 μM. Our results revealed that caffeic acid phenethyl ester showed anticancer potential against human and mouse pancreatic cancer cells in silico and significantly inhibited the viability, migration, and colony formation of ASML cells in vitro. © 2023 Society of Pharmaceutical Sciences of Ankara (FABAD). All rights reserved.
In Silico Drug Repurposing as Inhibitors Against Gsk-3β
(Hacettepe University, Faculty of Pharmacy, 2024) Deniz, E.; Karakuş, F.; Kuzu, B.
Tau, a protein associated with microtubules, is widely distributed throughout the central nervous system and promotes the polymerization, assembly, and stability of microtubules. Hyperphosphorylation of tau proteins leads to intracellular neurofibrillary tangles, which are the pathological hallmark of numerous neurodegenerative diseases and are collectively referred to as “tauopathies”. The most notable kinase identified in tau phosphorylation is glycogen synthase kinase 3 (GSK-3). Among the GSK-3 isoforms, GSK-3β has been linked to the pathophysiology of neurodegenerative diseases. Pharmacological inhibition of GSK-3β has been suggested as a potential therapeutic target for these diseases. In this study, the literature and databases were searched for potential inhibitory drugs against GSK-3β and 58 drugs were found. The drugs were filtered according to physicochemical-pharmacological properties and toxicity profiles via SwissADME, pkCSM, and ProTox-II, free web tools. After prefiltration, molecular docking was performed against GSK-3β with the remaining seven drugs (Nabumeton, Loxoprofen, Ketoprofen, Oxytetracycline, Benzoyl Peroxide, Naproxen, and Epinephrine Hydrochloride). According to the results, nabumetone had the best binding energy (-7.39 kcal/mol) and inhibition ability at the lowest concentration (3.8 µM) against GSK-3β among the seven drugs [compared to PF-04802367, a highly selective brain-penetrant kinase inhibitor]. Our results suggest that nabumetone may be a potential inhibitor of GSK-3β. © 2024, Hacettepe University, Faculty of Pharmacy. All rights reserved.
Possible Cardioprotective Mechanism of Action of Dexrazoxane, and Probable Human Topoisomerase Iiβ Inhibitors: an in Silico Analysis
(University of Ankara, 2022) Karakuş, F.; Kuzu, B.
Objective: The aim of this study was to determine which metabolite plays a role in the cardioprotective effect of dexrazoxane, and also to identify alternative compounds to dexrazoxane since clinical use of dexrazoxane is limited. For this purpose, the interactions of dexrazoxane and its three metabolites (B, C, and ADR-925), as well as the compounds, which reported to be inhibitors for topoisomerase VI (prototype of human DNA topoisomerase II beta), with human DNA topoisomerase II beta were investigated by molecular docking. Afterwards, the theoretical ADMET properties of all these compounds were determined Material and Method: The molecular structures were optimized by Gaussview 05 and Gaussian 03 package programs. AutoDock 4.2 software was used for molecular docking studies and the docking complexes were analyzed in 2D and 3D using the Discovery Studio Client 4.1 program. The pkCSM online program was used to calculate the theoretical ADMET parameters. Result and Discussion: As a result of molecular docking studies, it was determined that the B metabolite of dexrazoxane has a higher binding potential to human DNA topoisomerase II beta compared to both dexrazoxane and its other metabolites. The binding potentials of other compounds reported in the literature to human DNA topoisomerase II beta were radicicol>quinacrine>purpurin>9-Aminoacridine>hexylresorcinol, respectively. The results showed that the B metabolite of dexrazoxane plays an important role in the cardioprotective mechanism of action of dexrazoxane against anthracycline cardiotoxicity. In addition, it has been determined that other compounds, except purpurin, have the potential to cause toxicity. © 2022 University of Ankara. All rights reserved.
Trisubstituted Imidazole and N-Propargyl Imidazole Analogues: Synthesis, Characterization, in Silico Studies and Enzyme Inhibitory Properties
(Maik Nauka/interperiodica/springer, 2023) Altiok, M. S.; Cetin, A.; Kuzu, B.; Bildirici, I.
In recent years, the alpha-amylase, pancreatic lipase (PL), and beta-glucuronidase enzymes have received much attention as they promise to be potential drug targets for obesity and diabetes-related diseases. In this study, the synthesis and characterization of newly designed tricyclic imidazopyrrolopyrazine analogues with the potential to affect these enzymes were evaluated. The pharmacological evaluation of all imidazopyrrolopyrazine analogues revealed that all the synthesized analogues displayed excellent inhibitory effects against alpha-amylase, with the IC50 values of these analogues ranging from 4.05 +/- 0.7 to 5.61 +/- 0.8 mu M. The IC50 values of all synthesized analogues were also found to be effective inhibitors, ranging from 5.2 +/- 0.5 to 13.7 +/- 2.3 mu M, against pancreatic lipase. Furthermore, all analogues exhibited moderate inhibition in a wide range of 151.4 +/- 9.1 to 302.5 +/- 7.9 mu M against beta-glucuronidase. Additionally, all the synthesized analogues displayed moderate binding affinity with Ferric Reducing Antioxidant Power (FRAP), and low binding affinity with Oxygen Radical Absorbance Capacity (ORAC). This study provides valuable potential for the new tricyclic imidazopyrrolopyrazine analogues in further pharmacological studies.