Person: MUTLU, ÖZAL
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MUTLU
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ÖZAL
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Publication Open Access Hit identification against peptidyl-prolyl isomerase of Theileria annulata by combined virtual high-throughput screening and molecular dynamics simulation approach(2020-12-01) MUTLU, ÖZAL; Spahi S., MUTLU Ö., Sariyer E., Kocer S., Ugurel E., Turgut-Balik D.Theileria annulata secretes peptidyl prolyl isomerase enzyme (TaPIN1) to manipulate the host cell oncogenic signaling pathway by disrupting the tumor suppressor F-box and WD repeat domain-containing 7 (FBW7) protein level leading to an increased level of c-Jun proto-oncogene. Buparvaquone is a hydroxynaphthoquinone anti-theilerial drug and has been used to treat theileriosis. However, TaPIN1 contains the A53 P mutation that causes drug resistance. In this study, potential TaPIN1 inhibitors were investigated using a library of naphthoquinone derivatives. Comparative models of mutant (m) and wild type (wt) TaPIN1 were predicted and energy minimization was followed by structure validation. A naphthoquinone (hydroxynaphthalene-1,2-dione, hydroxynaphthalene-1,4-dione) and hydroxynaphthalene-2,3-dione library was screened by Schrödinger Glide HTVS, SP and XP docking methodologies and the docked compounds were ranked by the Glide XP scoring function. The two highest ranked docked compounds Compound 1 (4-hydroxy-3-[3,4,5-trihydroxy-6-(hydroxymethyl)oxan-2-yl]oxynaphthalene-1,2-dione) and Compound 2 (6-acetyl-1,4,5,7,8-pentahydroxynaphthalene-2,3-dione) were used for further molecular dynamics (MD) simulation studies. The MD results showed that ligand Compound 1 was located in the active site of both mTaPIN1 and wtTaPIN1 and could be proposed as a potential inhibitor by acting as a substrate antagonist. However, ligand Compound 2 was displaced away from the binding pocket of wtTaPIN1 but was located near the active site binding pocket of mTaPIN1 suggesting that could be selectively evaluated as a potential inhibitor against the mTaPIN1. Compound 1 and Compound 2 ligands are potential inhibitors but Compound 2 is suggested as a better inhibitor for mTaPIN1. These ligands could also further evaluated as potential inhibitors against human peptidyl prolyl isomerase which causes cancer in humans by using the same mechanism as TaPIN1.Publication Open Access Heterologous expression, biochemical characterisation and computational analysis of Bacteroides fragilis enolase(2022-06-01) MUTLU, ÖZAL; Ugurel E., Kocer S., Sariyer E., MUTLU Ö., Inci T. G., Ugurel O. M., Turgut-Balik D.© 2022Bacteriodes fragilis is an anaerobic bacterium found in the human intestinal flora. In this study, BfEno was targeted with a structure-based drug design approach because inhibition of this enzyme may prevent both the aerobic and anaerobic pathways due to its role in the glycolytic pathway. First, the gene encoding BfEno was cloned, expressed and the protein produced over 95% purity. The Km and Vmax values of BfEno were determined as 314.9 µM and 256.2 µmol/min.mg, respectively. Drug-like chemicals were retrieved from the ZINC database for high-throughput virtual screening analyses. As a result of screening study, the ZINC91441604 has been proposed to bind to the active site of the enzyme and remain stable. The same compound exhibited weak binding to the human enolases than the bacterial enolase. Hence, ZINC91441604 may be proposed as a novel candidate for further in vitro and in vivo drug analysis towards the treatment of B. fragilis infections.Publication Open Access Experimentation and analysis of powder injection molded Ti10Nb10Zr alloy: a promising candidate for electrochemical and biomedical application(ELSEVIER, 2019-11) GÜLSOY, HAMİT ÖZKAN; Yemisci, Isil; Mutlu, Ozal; Gulsoy, Nagihan; Kunal, Kate; Atre, Sundar; Gulsoy, H. OzkanThis paper describes the microstructural, mechanical and corrosion properties of injection molded Ti10Nb10Zr alloys. T10Nb10Zr powder was injection molded with wax-based binder. The critical powder loading for injection molding was 55 vol% for feedstock. Binder debinding was performed in solvent and thermal method. After debinding the samples were sintered at different temperatures and times in vacuum atmosphere (10-5 mbar) to obtain fully dense parts. Metallographic studies were conducted to determine the extent of densification and the corresponding microstructural changes. The electrochemical property and biocompatibility of the sintered samples were performed electrochemically, by selfbody -fluid immersion tests and cell culture experiments. The results show that Ti10Nb10Zr alloys could be sintered to a maximum 99% of theoretical density. Maximum ultimate tensile strength, elongation and hardness obtained were 748 MPa, 14.3 and 114 HRB respectively at 1500 degrees C for 3 h. Additionally, the sintered i10Nb10Zr alloys exhibited high mechanical and corrosion properties in a physiological environment. (C) 2019 The Author. Published by Elsevier B.V.Publication Open Access Identification of novel compounds against Acinetobacter baumannii 3-oxoacyl-[acyl-carrier-protein] synthase I (FabB) via comprehensive structure-based computational approaches.(2023-07-12) MUTLU, ÖZAL; Albayrak E., Koçer S., Mutlu Ö.Acinetobacter baumannii is one of the most serious opportunistic pathogens according to WHO. The difference between bacterial and mammalian fatty acid biosynthesis pathways makes FASII enzymes attractive targets in drug discovery. 3-oxoacyl-[acyl-carrier-protein] synthase I (FabB) from the FAS II pathway catalyze the condensation of malonyl ACP with acyl-ACP, and elongates the fatty acid chain by two carbons. To investigate potential inhibitors of the A. baumannii FabB, we used computational approaches including homology modeling, high-throughput virtual screening, molecular docking, molecular dynamics simulations, and MM-GBSA free energy calculations. After the high-throughput virtual screening, the resulting ligands were further screened using the QM-polarized ligand docking (QPLD) and induced fit docking (IFD) approaches. Molecular dynamics simulations were performed for 100 ns. And according to binding free energy calculations, we have identified nine compounds with the best binding affinities. Three of these compounds were selected for an additional 1 μs MD simulation to assess ligand stability. Two of them named L6 and L7 showed promised stability and affinity to the target. Here, we present novel compounds against A. baumannii FabB via structure-based computational approaches. These compounds might pave the way for the design of new lead structures and inhibitors for multidrug-resistant A. baumannii.Publication Open Access Toxicity of cadmium based and cadmium free quantum dots in primary cultured zebrafish hepatocytes(2020-07-01) BİLGİSEVEN, IRMAK; MUTLU, ÖZAL; GÜLSOY, NAGİHAN; Kaluç N., Bilgiseven I., Mutlu Ö., Gülsoy N.Quantum Dots (QDs) are one of the most im-portant nanomaterials in nanotechnology owing to their unique physicochemical properties. A conven-tional QD contains Cd2+ in its core and in order to reduce its toxicity Cd-core/ZnS-shell and Cd-free QDs were produced. However, ZnS shell was not found as protective as predicted. Also, still not much is known about the toxicity of Cd-free QD. In this paper, we evaluated and compared the cytotoxicity and genotoxicity of three types of QDs (Cd-based core, Cd-based core/shell, and Cd-free QDs) in pri-mary cultured zebrafish hepatocytes. We show that Cd-based QDs significantly decreased cell viability whereas Cd-Free QDs caused a significant increase in cell viability in 24h. Moreover, ZnS shell reduced Cd2+ ion release into the cell but did not effectively prevent the cell from cytotoxic or genotoxic effects of the QD. Although the effects of Cd-based and Cd-Free QDs on cell viability were different, they both induced reactive oxygen species (ROS) production, DNA strand breaks and Rad51 downregulation in primary cultured zebrafish hepatocytes, revealing that they induce oxidative stress in these cells. To the best of our knowledge, this is the first report on the comparative toxicity evaluation of Cd-based with core and core/shell type, Cd-free QDs and CdCl2 by assessing ROS production, DNA damage and Rad51 expression.Publication Open Access Targeting SARS-CoV-2 Nsp12/Nsp8 interaction interface with approved and investigational drugs: anin silicostructure-based approach(TAYLOR & FRANCIS INC, 2022-01-22) MUTLU, ÖZAL; Mutlu, Ozal; Ugurel, Osman Mutluhan; Sariyer, Emrah; Ata, Oguz; Inci, Tugba Gul; Ugurel, Erennur; Kocer, Sinem; Turgut-Balik, DilekIn this study, the Nsp12-Nsp8 complex of SARS-CoV-2 was targeted with structure-based and computer-aided drug design approach because of its vital role in viral replication. Sequence analysis of RNA-dependent RNA polymerase (Nsp12) sequences from 30,366 different isolates were analysed for possible mutations. FDA-approved and investigational drugs were screened for interaction with both mutant and wild-type Nsp12-Nsp8 interfaces. Sequence analysis revealed that 70.42% of Nsp12 sequences showed conserved P323L mutation, located in the Nsp8 binding cleft. Compounds were screened for interface interaction, any with XP GScores lower than -7.0 kcal/mol were considered as possible interface inhibitors. RX-3117 (fluorocyclopentenyl cytosine) and Nebivolol had the highest binding affinities in both mutant and wild-type enzymes, therefore they were selected and resultant protein-ligand complexes were simulated for analysis of stability over 100 ns. Although the selected ligands had partial mobility in the binding cavity, they were not removed from the binding pocket after 100 ns. The ligand RX-3117 remained in the same position in the binding pocket of the mutant and wild-type enzyme after 100 ns MD simulation. However, the ligand Nebivolol folded and embedded in the binding pocket of mutant Nsp12 protein. Overall, FDA-approved and investigational drugs are able to bind to the Nsp12-Nsp8 interaction interface and prevent the formation of the Nsp12-Nsp8 complex. Interruption of viral replication by drugs proposed in this study should be further tested to pave the way forin vivostudies towards the treatment of COVID-19. Communicated by Ramaswamy H. SarmaPublication Open Access Kinetic Analysis of the Amino Terminal End of Active Site Loop of Lactate Deyhdrogenase from Plasmodium Vivax(GALENOS YAYINCILIK, 2012-12-22) MUTLU, ÖZAL; Mutlu, Ozal; Turgut-Balik, DilekObjective: In this study, kinetic analysis was performed to understand the functional importance of the amino terminal of the active site of previously mutated Plasmodium vivax Lactate Dehydrogenase enzyme by mimicking Toxoplasma gondii I, II, Eimeria acervulina and Eimeria tenella LDH's. Material and Methods: Mutant LDH genes were amplified by PCR and 6xHistag was added to the C-terminal of the enzymes. Then LDH enzymes are overproduced as recombinant in E. coli cells, purified by Ni-NTA agarose matrix and kinetic properties were analysed. Results: Observing increase of K-m values of mutant enzymes showed that mutations in this place caused decreasing affinity of enzyme for its substrate. However k(cat) values were about the same throughout all mutant proteins. Conclusion: Sensitivity of the studied region emphasizes the significance of this site for drug design studies for both Plasmodium and some other Apicomplexans.Publication Open Access Evaluation of the potency of FDA-approved drugs on wild type and mutant SARS-CoV-2 helicase (Nsp13)(ELSEVIER, 2020-11) MUTLU, ÖZAL; Ugurel, Osman Mutluhan; Mutlu, Ozal; Sariyer, Emrah; Kocer, Sinem; Ugurel, Erennur; Inci, Tugba Gul; Ata, Oguz; Turgut-Balik, DilekSARS-CoV-2 has caused COVID-19 outbreak with nearly 2 M infected people and over 100K death worldwide, until middle of April 2020. There is no confirmed drug for the treatment of COVID-19 yet. As the disease spread fast and threaten human life, repositioning of FDA approved drugs may provide fast options for treatment. In this aspect, structure-based drug design could be applied as a powerful approach in distinguishing the viral drug target regions from the host. Evaluation of variations in SARS-CoV-2 genome may ease finding specific drug targets in the viral genome. In this study, 3458 SARS-CoV-2 genome sequences isolated from all around the world were analyzed. Incidence of C17747T and A17858G mutations were observed to be much higher than others and they were on Nsp13, a vital enzyme of SARS-CoV-2. Effect of these mutations was evaluated on protein-drug interactions using in silico methods. The most potent drugs were found to interact with the key and neighbor residues of the active site responsible from ATP hydrolysis. As result, cangrelor, fludarabine, folic acid and polydatin were determined to be the most potent drugs which have potency to inhibit both the wild type and mutant SARS-CoV-2 helicase. Clinical data supporting these findings would be important towards overcoming COVID-19. (C) 2020 Elsevier B.V. All rights reserved.