Person: MUTLU, ÖZAL
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MUTLU
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ÖZAL
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Publication Metadata only Computational insight into the phthalocyanine-DNA binding via docking and molecular dynamics simulations(ELSEVIER SCI LTD, 2018) MUTLU, ÖZAL; Ozalp, Lalehan; Erdem, Safiye Sag; Yuce-Dursun, Basak; Mutlu, Ozal; Ozbil, MehmetPhthalocyanines are considered as good DNA binders, which makes them promising anti-tumor drug leads. The purpose of this study is to investigate the interactions between DNA and quaternary metallophthalocyanine derivatives (Q-MPc) possessing varying metals (M = Zn, Ni, Cu, Fe, Mg and Ca) by molecular docking since there seems to be a lack of information in the literature regarding this issue. In this direction, Autodock Vina and Molegro Virtual Docker programs were employed. Autodock Vina results reveal that each Q-MPc derivative binds to DNA strongly with similar binding energies and almost identical binding modes. They bind to the grooves of DNA by constituting favorable interactions between phosphate groups of DNA and Q-MPcs. Although changing the metal has no significant effect on binding, presence of quaternary amine substituents increases the binding constant K-b by about 2-fold comparing to the core Pc (ZnPc). Contrary to Autodock Vina, the calculated Molegro Virtual Docker binding scores have been more diverse indicating that the scoring function of Molegro is better in differentiating these metals. Despite the fact that Molegro is superior to Autodock Vina in terms of metal characterization, Autodock Vina and Molegro exhibit similar binding sites for the studied metallophthalocyanines. We propose that Q-MPc derivatives designed in this study are promising anti-tumor lead compounds since they tightly bind to DNA with considerably high K-b values. Cationic substituents and presence of metal have both positive effects on DNA binding which is critical for designing DNA-active drugs. Additional calculations employing molecular dynamics (MD) simulations verified the stability of Q-MPc-DNA complexes which remained in contact after 20 ns via attractive interactions mainly between DNA backbone and the Pc metal center.Publication Metadata only Biochemical and in silico Characterization of Recombinant L-Lactate Dehydrogenase of Theileria annulata(HUMANA PRESS INC, 2016) MUTLU, ÖZAL; Nural, Belma; Erdemir, Aysegul; Mutlu, Ozal; Yakarsonmez, Sinem; Danis, Ozkan; Topuzogullari, Murat; Turgut-Balik, DilekTheileria annulata is a parasite that causes theileriosis in cattle. Reports about drug resistance made essential to develop new drug. LDH of Theileria schizonts is the vital enzyme for its anaerobic metabolism. TaLDH gene was first cloned into pGEM-T cloning vector with two introns in our previous study. Here we report cloning of TaLDH without introns into pLATE 31 vector in E. coli BL21(DE3). Protein was in an inactive form. Two mutations were fixed to express the active protein. Protein was purified by affinity chromatography and evaluated by SDS-PAGE and size exclusion chromatography. Optimum pH of enzyme was performed in pH 7.5, and enzyme was stabilized at 20-40 A degrees C. Enzyme kinetics of recombinant TaLDH were found to be in the direction of pyruvate to lactate K (m) 0.1324 and K (i) 4.295 mM, k (cat) , 44.55/s and k (cat) /K (m) , 3.3693 x 10(5)/M/s. 3D structure of TaLDH was predicted, and possible drug binding sites were determined by homology modelling.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 Metadata only Effect of Zr, Nb and Ti addition on injection molded 316L stainless steel for bio-applications: Mechanical, electrochemical and biocompatibility properties(ELSEVIER SCIENCE BV, 2015) GÜLSOY, HAMİT ÖZKAN; Gulsoy, H. Ozkan; Pazarlioglu, Serdar; Gulsoy, Nagihan; Gundede, Busra; Mutlu, OzalThe research investigated the effect of Zr, Nb and Ti additions on mechanical, electrochemical properties and biocompatibility of injection molded 316L stainless steel. Addition of elemental powder is promoted to get high performance of sintered 316L stainless steels. The amount of additive powder plays a role in determining the sintered microstructure and all properties. In this study, 316L stainless steel powders used with the elemental Zr, Nb and Ti powders. A feedstock containing 62.5 wt% powders loading was molded at different injection molded temperature. The binders were completely removed from molded components by solvent and thermal debinding at different temperatures. The debinded samples were sintered at 1350 degrees C for 60 min. Mechanical, electrochemical property and biocompatibility of the sintered samples were performed mechanical, electrochemical, SBF immersion tests and cell culture experiments. Results of study showed that sintered 316L and 316L with additives samples exhibited high corrosion properties and biocompatibility in a physiological environment. (C) 2015 Elsevier Ltd. All rights reserved.Publication Metadata only Identification of benzamide inhibitors of histone deacetylase 1 from Babesia and Theileria species via high-throughput virtual screening and molecular dynamics simulations(SPRINGER, 2021) MUTLU, ÖZAL; Gurboga, Merve; Kugu, Gizem; Kamberaj, Hiqmet; Mutlu, OzalTheileria and Babesia species are eukaryotic protozoan parasites classified under the order Piroplasmida of the phylum Apicomplexa. Tick vectors transmit these microorganisms in tropical and subtropical regions to a wide range of animals, including ruminants, causing fatal and life-threatening diseases such as bovine babesiosis and theileriosis. Resistance to commercially available drugs requires the search for new drug candidates. Histone deacetylase (HDAC) has a potential to be utilized as a drug target; therefore, it may be considered as an effective alternative. Previous studies revealed that HDAC inhibitors, identified for human use, show promising anti-parasitic effects. We have herein focused on the class I HDAC enzyme, HDAC1, of the Babesia and Theileria species to discover potential benzamide inhibitors by following a streamlined workflow of computer-aided drug design methodology. Molecular docking and molecular dynamics simulations revealed that benzamide derivatives stably interacted with the HDAC1 active site in both parasites as hypothesized. Furthermore, specific residue insertions at the entry point of the active site cleft of parasitic HDAC1 could enable ways to design parasite-specific drugs without adversely affecting host enzymes.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 Metadata only Functional analyses of dipeptide and pentapeptide insertions on Theileria annulata enolase by site-directed mutagenesis and in silico approaches(ELSEVIER SCIENCE BV, 2019) MUTLU, ÖZAL; Yakarsonmez, Sinem; Cengiz, Ebru Cayir; Mutlu, Ozal; Turgut-Balik, DilekTheileria annulata enolase (TaENO) could be assessed as a druggable target for tropical theileriosis treatment. The parasite enzyme plays an important role in many cellular functions and carries some structural differences like dipeptide (262EK263) and pentapeptide ((103)EWGYC(107)) insertions from the host enzyme, Bos taurus enolase. In this study, the functional effects of these insertions on TaENO activity were analyzed by in vitro site-directed mutagenesis and in silico molecular docking analyses for the first time in the literature. In vitro results showed that, although the deletion of the pentapeptide insertion (TaENO Delta EWGYC) reduced the enzyme activity slightly, the removal of the dipeptide insertion (TaENO Delta EK) halted it. Also, molecular docking results revealed that the deletion of these insertions affected the substrate binding affinity of the mutant enzymes. The active site of TaENO Delta EK exhibited a small decrease of substrate binding affinity compared to the active site of TaENO Delta EWGYC relative to the wild type TaENO. Although we conclude that both regions could be evaluated as possible drug-binding sites to inhibit TaENO in further studies, these results indicate that the dipeptide insertion could be a more promising drug binding site than the pentapeptide insertion.Publication Metadata only Novel hydroxyapatite/graphene oxide/collagen bioactive composite coating on Ti16Nb alloys by electrodeposition(ELSEVIER SCIENCE BV, 2019) GÜLSOY, HAMİT ÖZKAN; Yilmaz, Eren; Cakiroglu, Bekir; Gokce, Azim; Findik, Fehim; Gulsoy, H. Ozkan; Gulsoy, Nagihan; Mutlu, Ozal; Ozacar, MahmutA novel implant coating material containing graphene oxide (GO) and collagen (COL), and hydroxyapatite (HA) was fabricated with the aid of tannic acid by electrodeposition. The surface of Ti16Nb alloy was subjected to anodic oxidation, and then HA-GO coating was applied to Ti16Nb surface by cathodic method. Then, COL was deposited on the surface of the HA-GO coating by the biomimetic method. HA, HA-GO, HA-GO-COL coatings on the surface of the Ti16Nb alloy have increased the corrosion resistance by the formation of a barrier layer on the surface. For HA-GO-COL coating, the highest corrosion resistance is obtained due to the compactness and homogeneity of the coating structure. The contact angle of the bare Ti16Nb is approximately 65 degrees, while the contact angle of the coated samples is close to 0 degrees. Herein, the increased surface wettability is important for cell adhesion. The surface roughness of the uncoated Ti16Nb alloy was between 1 and 3 mu m, while the surface roughness of the coated surfaces was measured between 20 and 110 mu m. The contact between the bone and the implant has been improved. Graphene oxide-containing coatings have improved the antibacterial properties compared to the GO-free coating using S. aureus. The hardness and elastic modulus of the coatings were measured by the nanoindentation test, and the addition of GO and collagen to the HA coating resulted in an increase in strength. The addition of GO to the HA coating reduced the viability of 3 T3 fibroblast cells, whereas the addition of collagen to HA-GO coat increased the cell adhesion and viability.
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